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Zhang Y, Naaz A, Cheng TYN, Lin JJ, Gao M, Dorajoo R, Alfatah M. Systematic transcriptomics analysis of calorie restriction and rapamycin unveils their synergistic interaction in prolonging cellular lifespan. Commun Biol 2025; 8:753. [PMID: 40369174 PMCID: PMC12078523 DOI: 10.1038/s42003-025-08178-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 05/06/2025] [Indexed: 05/16/2025] Open
Abstract
Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to the development of age-related diseases. In the pursuit of slowing or even reversing the aging process, a prominent strategy of significant interest is calorie restriction (CR), also known as dietary restriction, and the potential influence of a drug called rapamycin (RM). Both CR and RM have demonstrated the capacity to extend healthspan and lifespan across a diverse array of species, including yeast, worms, flies, and mice. Nevertheless, their individual and combined effects on mitotic and postmitotic cells, as well as their comparative analysis, remain areas that demand a thorough investigation. In this study, we employ RNA-sequencing methodologies to comprehensively analyze the impact of CR, RM, and their combination (CR + RM) on gene expression in yeast cells. Our analysis uncovers distinctive, overlapping, and even contrasting patterns of gene regulation, illuminating the unique and shared effects of CR and RM. Furthermore, the transcriptional synergistic interaction of CR + RM is validated in extending the lifespan of both yeast and human cells.
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Affiliation(s)
- Yizhong Zhang
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Arshia Naaz
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Trishia Yi Ning Cheng
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Jovian Jing Lin
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
| | - Mingtong Gao
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore
| | - Rajkumar Dorajoo
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Mohammad Alfatah
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore.
- Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Centre for Healthy Longevity, National University Health System, Singapore, Singapore.
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2
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Mazzilli R, Zamponi V, Mancini C, Giorgini B, Golisano B, Mikovic N, Pecora G, Russo F, Martiradonna M, Paravani P, Prosperi D, Faggiano A. Neuroendocrine tumors and diabetes mellitus: which treatment and which effect. Endocrine 2025; 88:36-50. [PMID: 39752043 DOI: 10.1007/s12020-024-04149-9] [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: 08/28/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025]
Abstract
Diabetes mellitus (DM) and neuroendocrine tumors (NET) can exert unfavorable effects on each other prognosis. In this narrative review, we evaluated the effects of NET therapies on glycemic control and DM management and the effects of anti-diabetic therapies on NET outcome and management. For this purpose, we searched the PubMed, Science Direct, and Google Scholar databases for studies reporting the effects of NET therapy on DM as well as the effect of DM therapy on NET. The majority of NET treatments appear to impair glycaemic control, both inducing hypoglycemic or, more commonly, hyperglycemia and even new-onset DM. However, glucose metabolism imbalance can be effectively managed by modulating anti-diabetic therapy and adopting an appropriate nutritional approach. On the other hand, the effects of anti-diabetic treatment, like insulin, sulfonylureas, thiazolidinediones, ipeptidyl-peptidase-4 inhibitors, Glucagon-like peptide-1 receptor agonists, and Sodium-glucose cotransporter-2 inhibitors on NET are unclear. Recently, metformin has been investigated in patients with gastroenteropancreatic NET resulting in improved progression free survival suggesting a potential antineoplastic role. Finally, the management of DM in patients with NET is of great clinical relevance to correctly perform radiological procedures and even more functional imaging procedures, as well as to optimize the therapy and avoid treatment withdrawal or discontinuation. In conclusion, understanding the mechanisms underlying therapy-induced DM and implementing appropriate monitoring and management strategies of DM are essential for optimizing NET patient outcome and quality of life.
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Affiliation(s)
- Rossella Mazzilli
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy.
| | - Virginia Zamponi
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Camilla Mancini
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Beatrice Giorgini
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Bianca Golisano
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Nevena Mikovic
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Giulia Pecora
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Flaminia Russo
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Maurizio Martiradonna
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Piero Paravani
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
| | - Daniela Prosperi
- Unit of Nuclear Medicine, ENETS Center of Excellence, Sant'Andrea University Hospital, Rome, Italy
| | - Antongiulio Faggiano
- Unit of Endocrinology, Department of Clinical and Molecular Medicine, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy
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Golpasandi H, Rahimi MR. The Effect of Vitamin D3 Injection Combined With High-Intensity Interval Training on Excessive Autophagy in the Heart Tissue of Type 2 Diabetes-Induced Rats: An Analysis of the mTOR-Beclin-1-Fyco-1-Cathepsin D Pathway. Cardiovasc Ther 2025; 2025:8817195. [PMID: 40144137 PMCID: PMC11944841 DOI: 10.1155/cdr/8817195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 02/28/2025] [Indexed: 03/28/2025] Open
Abstract
Introduction: This study investigated the effect of vitamin D3 injection combined with high-intensity interval training on cell signaling pathways involved in excessive autophagy, specifically the mTOR (mechanistic target of rapamycin)-Beclin-1-Fyco-1 (FYVE and coiled-coil domain-containing protein 1)-cathepsin D pathway, in the heart tissue of Type 2 diabetes-induced rats. Method: In this experimental study, 32 male Wistar rats were fed a high-fat diet for 6 weeks to induce Type 2 diabetes, followed by a single subcutaneous injection of 35 mg/kg streptozotocin (STZ). The rats were then randomly assigned to one of four groups: (1) diabetes control (DC), (2) diabetes + HIIT (DT), (3) diabetes + vitamin D3 (DV), and (4) diabetes + HIIT + vitamin D3 (DTV). HIIT sessions were conducted for 8 weeks, five times per week, at an intensity of 85%-95% of maximum running speed (V max), while vitamin D3 was administered weekly via subcutaneous injection at a dose of 10,000 IU/kg. Twenty-four hours after the intervention period, heart and left ventricular tissues were collected for analysis of the levels of autophagy signaling proteins mTOR, phosphorylated mechanistic target of rapamycin (pmTOR), Beclin-1, Fyco-1, and cathepsin D. Results: Two-way ANOVA revealed that Type 2 diabetes significantly increased the levels of Beclin-1, Fyco-1, and cathepsin D (p < 0.001) while significantly reducing the levels of mTOR and pmTOR (p < 0.001). HIIT, vitamin D3 injection, and their combined treatment significantly decreased the levels of Beclin-1, Fyco-1, and cathepsin D and increased the levels of mTOR and pmTOR compared to the diabetes control group (p < 0.001). Conclusion: Type 2 diabetes increases autophagy in the left ventricle, marked by altered levels of key autophagy proteins. HIIT and vitamin D3 injections mitigate these effects by enhancing mTOR signaling and reducing excessive autophagy. These interventions show promise as nonpharmacological strategies to improve cardiac health in Type 2 diabetes and could be incorporated into clinical and rehabilitation programs.
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Affiliation(s)
- Hadi Golpasandi
- Department of Exercise Physiology, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Iran
| | - Mohammad Rahman Rahimi
- Department of Exercise Physiology, Faculty of Humanities and Social Sciences, University of Kurdistan, Sanandaj, Iran
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Zhang Y, Wang H, Xu C, Ye X, Nan Y, Hu X, Fan J, Wang X, Ju D. Rubicon siRNA-encapsulated liver-targeting nanoliposome is a promising therapeutic for non-alcoholic fatty liver disease. Int J Pharm 2025; 672:125291. [PMID: 39880145 DOI: 10.1016/j.ijpharm.2025.125291] [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: 07/09/2024] [Revised: 01/01/2025] [Accepted: 01/26/2025] [Indexed: 01/31/2025]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a prevalent metabolic liver disorder worldwide, and effective therapeutic strategies for its treatment remains limited. In this article, we introduced Glipo-siRubi, a hepatocytes-targeting RNA interference (RNAi) nanoliposome for suppression of Rubicon expression, aiming to achieve precise regulation of autophagy in NAFLD. Autophagy activation induced by Rubicon suppression resulted in reduced endoplasmic reticulum stress and intracellular lipid accumulation in vitro. Moreover, Glipo-siRubi administration exhibited remarkable therapeutic efficacy, characterized by decreased liver lipid accumulation, ameliorated histopathology and improved insulin sensitivity in mice with western diet, indicating its notable potential against NAFLD. By inducing autophagy activation, the hepatocytes-targeting Glipo-siRubi provided a promising method for NAFLD treatment, addressing the limitations of current approaches. Our study highlighted the significance of Rubicon-specific suppression in NAFLD treatment, offering a specific, safe, and efficient approach to mitigate NAFLD.
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Affiliation(s)
- Yuting Zhang
- Minhang Hospital Fudan University Shanghai China; Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
| | - Hanqi Wang
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
| | - Caili Xu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
| | - Xiaomiao Ye
- Minhang Hospital Fudan University Shanghai China.
| | - Yanyang Nan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
| | - Xiaozhi Hu
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
| | - Jiajun Fan
- Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China; Shanghai Hailu Biological Technology Co., Ltd, Shanghai 201200 China.
| | - Xuebin Wang
- Department of Pharmacy, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Dianwen Ju
- Minhang Hospital Fudan University Shanghai China; Department of Biological Medicines & Shanghai Engineering Research Center of Immunotherapeutics Fudan University School of Pharmacy Shanghai China.
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Mu-u-min RBA, Diane A, Allouch A, Al-Siddiqi HH. Immune Evasion in Stem Cell-Based Diabetes Therapy-Current Strategies and Their Application in Clinical Trials. Biomedicines 2025; 13:383. [PMID: 40002796 PMCID: PMC11853723 DOI: 10.3390/biomedicines13020383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 01/28/2025] [Accepted: 02/03/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Human pancreatic islet transplantation shows promise for long-term glycemic control in diabetes patients. A shortage of healthy donors and the need for continuous immunosuppressive therapy complicates this. Enhancing our understanding of the immune tolerance mechanisms related to graft rejection is crucial to generate safer transplantation strategies. This review will examine advancements in immune protection strategies for stem cell-derived islet therapy and discuss key clinical trials involving stem cell-derived β-cells and their protective strategies against the host immune system. Methods: A comprehensive literature search was performed on peer-reviewed publications on Google Scholar, Pubmed, and Scopus up to September 2024 to extract relevant studies on the various strategies of immune evasion of stem cell-derived β-cells in humans. The literature search was extended to assimilate all relevant clinical studies wherein stem cell-derived β-cells are transplanted to treat diabetes. Results: Our analysis highlighted the importance of human pluripotent stem cells (hPSCs) as a potentially unlimited source of insulin-producing β-cells. These cells can be transplanted as an effective source of insulin in diabetes patients if they can be protected against the host immune system. Various strategies of immune protection, such as encapsulation and genetic manipulation, are currently being studied and clinically tested. Conclusions: Investigating immune tolerance in hPSC-derived islets may help achieve a cure for diabetes without relying on exogenous insulin. Although reports of clinical trials show promise in reducing insulin dependency in patients, their safety and efficacy needs to be further studied to promote their use as a long-term solution to cure diabetes.
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Affiliation(s)
- Razik Bin Abdul Mu-u-min
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
| | - Abdoulaye Diane
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
| | - Asma Allouch
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar;
| | - Heba Hussain Al-Siddiqi
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar; (A.D.); (H.H.A.-S.)
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Orr C, Stratton J, El-Shahawy M, Forouhar E, Peng A, Singh G, Omori K, Qi M, Kandeel F. Impact of Tacrolimus, Sirolimus, Age, and Body Mass Index on the Occurrence of Skin Cancer and Islet Dysfunction After Transplantation. Cell Transplant 2025; 34:9636897241309412. [PMID: 39780302 PMCID: PMC11713960 DOI: 10.1177/09636897241309412] [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: 06/23/2024] [Revised: 11/27/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Herein, we characterized the percentage of tacrolimus to the combined sirolimus and tacrolimus trough levels (tacrolimus %) observed during islet transplant-associated immune suppression therapy with post-transplant skin cancer. Although trough levels of tacrolimus and sirolimus were not different (P = 0.79, 0.73, respectively), high tacrolimus % resulted in a 1.32-fold increase in skin cancer odds when adjusting for age, sex, body mass index (BMI), and use of mycopheonlate mofetil (MMF; p = 0.039). Skin cancer patients were likely to have been older but not differ significantly (mean difference 12 years, P = 0.056), but age was significantly associated with a 1.22-fold increase in adjusted skin cancer odds (P = 0.046). BMI was inversely associated with skin cancer, with an adjusted odds ratio (OR) of 0.40 (P = 0.022). High tacrolimus % (>35) resulted in a 4.6-fold increase in skin cancer frequency, whereas sirolimus above 75% of the combined therapy led to a 5.2-fold increase in islet graft dysfunction (IGD) events/year. By calculating the maximum safe exposure (MSE) to tacrolimus % according to patient age and BMI, we found that cumulative months spent above MSE was predictive of skin cancer (1.20-fold increase, P = 0.003). Individuals exceeding the MSE for 1 year were 9.2 times more likely to develop skin cancer (P = 0.008). Results suggest that strategies targeting immunosuppression ratios based on age and BMI may minimize cancer risk while improving graft survival and function.
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Affiliation(s)
- Christopher Orr
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Jeannette Stratton
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Mohamed El-Shahawy
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Elena Forouhar
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Alice Peng
- Kidney & Pancreas Transplant Program, Cedars-Sinai Medical Center, Los Angeles, CA. USA
| | - Gagandeep Singh
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Keiko Omori
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Meirigeng Qi
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute, City of Hope, Duarte, CA, USA
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Ato S, Oya C, Ogasawara R. Rapamycin administration causes a decrease in muscle contractile function and systemic glucose intolerance concomitant with reduced skeletal muscle Rictor, the mTORC2 component, expression independent of energy intake in young rats. PLoS One 2024; 19:e0312859. [PMID: 39637031 PMCID: PMC11620399 DOI: 10.1371/journal.pone.0312859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/14/2024] [Indexed: 12/07/2024] Open
Abstract
Emerging evidence suggests the potential of rapamycin, an antibiotic from Streptomyces hygroscopicus that functions as a mechanistic target of rapamycin (mTOR) inhibitor, as a mimetic of caloric restriction (CR) for maintaining skeletal muscle health. Several studies showed that rapamycin administration (RAP) reduced appetite and energy intake. However, the physiological and molecular differences between RAP and CR in skeletal muscle are not fully understood. Here we observed the effects of 4 weeks of RAP administration and CR corresponding to the reduction in energy intake produced by RAP administration (PF, paired feeding) on fast glycolytic and slow oxidative muscle in young adult rats. We found that 4 weeks of RAP demonstrated low fast-glycolytic muscle mass with smaller type I and IIb/x myofiber size independent of the energy intake. In addition, PF improved the contractile function of the plantar flexor muscle, whereas RAP did not improve its function. The suppressing response of mTORC1 signaling to RAP is greater in slow-oxidative muscles than in fast-glycolytic muscles. In addition, systemic glucose tolerance was exacerbated by RAP, with reduced expression of Rictor and hexokinase in skeletal muscle. These observations imply that RAP may have a slight but significant negative impact and it obviously different to CR in young adult skeletal muscle.
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Affiliation(s)
- Satoru Ato
- Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
- Faculty of Health and Sports Sciences, Toyo University, Tokyo, Japan
| | - Chieri Oya
- Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan
| | - Riki Ogasawara
- Department of Life Science and Applied Chemistry, Nagoya Institute of Technology, Nagoya, Japan
- Healthy Food Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan
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Zaidalkilani AT, Al‐kuraishy HM, Fahad EH, Al‐Gareeb AI, Elewa YHA, Zahran MH, Alexiou A, Papadakis M, AL‐Farga A, Batiha GE. Autophagy modulators in type 2 diabetes: A new perspective. J Diabetes 2024; 16:e70010. [PMID: 39676616 PMCID: PMC11647182 DOI: 10.1111/1753-0407.70010] [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: 07/13/2023] [Revised: 05/31/2024] [Accepted: 08/27/2024] [Indexed: 12/17/2024] Open
Abstract
Type 2 diabetes (T2D) is a chronic metabolic disorder caused by defective insulin signaling, insulin resistance, and impairment of insulin secretion. Autophagy is a conserved lysosomal-dependent catabolic cellular pathway involved in the pathogenesis of T2D and its complications. Basal autophagy regulates pancreatic β-cell function by enhancing insulin release and peripheral insulin sensitivity. Therefore, defective autophagy is associated with impairment of pancreatic β-cell function and the development of insulin rersistance (IR). However, over-activated autophagy increases apoptosis of pancreatic β-cells leading to pancreatic β-cell dysfunction. Hence, autophagy plays a double-edged sword role in T2D. Therefore, the use of autophagy modulators including inhibitors and activators may affect the pathogenesis of T2D. Hence, this review aims to clarify the potential role of autophagy inhibitors and activators in T2D.
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Affiliation(s)
- Ayah Talal Zaidalkilani
- Department of Nutrition, Faculty of Pharmacy and Medical SciencesUniversity of PetraAmmanJordan
| | - Hayder M. Al‐kuraishy
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Al‐Mustansiriyah UniversityBaghdadIraq
| | - Esraa H. Fahad
- Department of Pharmacology and ToxicologyCollege of Pharmacy, Mustansiriyah UniversityBaghdadIraq
| | - Ali I. Al‐Gareeb
- Department of Clinical Pharmacology and MedicineCollege of Medicine, Al‐Mustansiriyah UniversityBaghdadIraq
| | - Yaser Hosny Ali Elewa
- Department of Histology and Cytology, Faculty of Veterinary MedicineZagazig UniversityZagazigEgypt
- Faculty of Veterinary MedicineHokkaido UniversitySapporoJapan
| | | | - Athanasios Alexiou
- University Centre for Research & Development, Chandigarh UniversityMohaliPunjabIndia
- Department of Research & DevelopmentFunogenAthensGreece
- Department of Research & DevelopmentAFNP MedWienAustria
- Department of Science and EngineeringNovel Global Community Educational FoundationHebershamNew South WalesAustralia
| | - Marios Papadakis
- Department of Surgery IIUniversity Hospital Witten‐HerdeckeWuppertalGermany
| | - Ammar AL‐Farga
- Department of BiochemistryCollege of Science University of JeddahJeddahSaudi Arabia
| | - Gaber El‐Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary MedicineDamanhur UniversityDamanhurAlBeheiraEgypt
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Al-kuraishy HM, Jabir MS, Al-Gareeb AI, Klionsky DJ, Albuhadily AK. Dysregulation of pancreatic β-cell autophagy and the risk of type 2 diabetes. Autophagy 2024; 20:2361-2372. [PMID: 38873924 PMCID: PMC11572262 DOI: 10.1080/15548627.2024.2367356] [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: 10/12/2023] [Accepted: 06/08/2024] [Indexed: 06/15/2024] Open
Abstract
Macroautophagy/autophagy is an essential degradation process that removes abnormal cellular components, maintains homeostasis within cells, and provides nutrition during starvation. Activated autophagy enhances cell survival during stressful conditions, although overactivation of autophagy triggers induction of autophagic cell death. Therefore, early-onset autophagy promotes cell survival whereas late-onset autophagy provokes programmed cell death, which can prevent disease progression. Moreover, autophagy regulates pancreatic β-cell functions by different mechanisms, although the precise role of autophagy in type 2 diabetes (T2D) is not completely understood. Consequently, this mini-review discusses the protective and harmful roles of autophagy in the pancreatic β cell and in the pathophysiology of T2D.
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Affiliation(s)
- Hayder M. Al-kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
| | - Majid S. Jabir
- Department of Applied Science, University of Technology- Iraq, Baghdad, Iraq
| | - Ali I. Al-Gareeb
- Department of Clinical Pharmacology and Medicine, Jabir ibn Hayyan Medical University, Al-Ameer Qu./Najaf, Kufa, Iraq
| | | | - Ali K. Albuhadily
- Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq
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10
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Asiri A, Al Qarni A, Bakillah A. The Interlinking Metabolic Association between Type 2 Diabetes Mellitus and Cancer: Molecular Mechanisms and Therapeutic Insights. Diagnostics (Basel) 2024; 14:2132. [PMID: 39410536 PMCID: PMC11475808 DOI: 10.3390/diagnostics14192132] [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: 08/25/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 10/20/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) and cancer share common risk factors including obesity, inflammation, hyperglycemia, and hyperinsulinemia. High insulin levels activate the PI3K/Akt/mTOR signaling pathway promoting cancer cell growth, survival, proliferation, metastasis, and anti-apoptosis. The inhibition of the PI3K/Akt/mTOR signaling pathway for cancer remains a promising therapy; however, drug resistance poses a major problem in clinical settings resulting in limited efficacy of agents; thus, combination treatments with therapeutic inhibitors may solve the resistance to such agents. Understanding the metabolic link between diabetes and cancer can assist in improving the therapeutic strategies used for the management of cancer patients with diabetes and vice versa. This review provides an overview of shared molecular mechanisms between diabetes and cancer as well as discusses established and emerging therapeutic anti-cancer agents targeting the PI3K/Akt/mTOR pathway in cancer management.
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Affiliation(s)
- Abutaleb Asiri
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ali Al Qarni
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
| | - Ahmed Bakillah
- King Abdullah International Medical Research Center (KAIMRC), Eastern Region, Al Ahsa 36428, Saudi Arabia; (A.A.); (A.A.Q.)
- Division of Medical Research Core-A, King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), Al Ahsa 36428, Saudi Arabia
- King Abdulaziz Hospital, Ministry of National Guard-Health Affairs (MNG-HA), Al Ahsa 36428, Saudi Arabia
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Liu T, Zhang J, Chang F, Sun M, He J, Ai D. Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischaemia in type 2 diabetes. Cardiovasc Res 2024; 120:1218-1234. [PMID: 38722901 DOI: 10.1093/cvr/cvae105] [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: 07/28/2023] [Revised: 03/08/2024] [Accepted: 03/17/2024] [Indexed: 09/03/2024] Open
Abstract
AIMS Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM. METHODS AND RESULTS Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. CONCLUSION Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM.
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Affiliation(s)
- Ting Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Jiachen Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Fangyuan Chang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Mengyu Sun
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jinlong He
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
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12
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Jain AB, Lai V. Medication-Induced Hyperglycemia and Diabetes Mellitus: A Review of Current Literature and Practical Management Strategies. Diabetes Ther 2024; 15:2001-2025. [PMID: 39085746 PMCID: PMC11330434 DOI: 10.1007/s13300-024-01628-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024] Open
Abstract
With the increasing global incidence of diabetes mellitus, physicians may encounter more patients with acute and chronic complications of medication-induced hyperglycemia and diabetes. Moreover, medication-induced diabetes may be an important contributing factor to the high rates of diabetes, and recognizing its impact and risk is a critical step in curtailing its effect on the global population. It has long been recognized that multiple classes of medications are associated with hyperglycemia through various mechanisms, and the ability to foresee this and implement adequate management strategies are important. Moreover, different antihyperglycemic medications are better suited to combat the hyperglycemia encountered with different classes of medications, so it is critical that physicians can recognize which agents should be used, and which medications to avoid in certain types of medication-induced hyperglycemia. In this review, we will discuss the evidence behind the main classes of medications that cause hyperglycemia, their mechanism of action, specific agents that are associated with worsened glycemic control, and, most importantly, management strategies that are tailored to each specific class.
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Affiliation(s)
- Akshay B Jain
- Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
| | - Valerie Lai
- Division of Endocrinology and Metabolism, Department of Medicine, University of Calgary, Calgary, AB, Canada
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13
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Das F, Ghosh-Choudhury N, Kasinath BS, Sharma K, Choudhury GG. High glucose-induced downregulation of PTEN-Long is sufficient for proximal tubular cell injury in diabetic kidney disease. Exp Cell Res 2024; 440:114116. [PMID: 38830568 DOI: 10.1016/j.yexcr.2024.114116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 04/24/2024] [Accepted: 05/31/2024] [Indexed: 06/05/2024]
Abstract
During the progression of diabetic kidney disease, proximal tubular epithelial cells respond to high glucose to induce hypertrophy and matrix expansion leading to renal fibrosis. Recently, a non-canonical PTEN has been shown to be translated from an upstream initiation codon CUG (leucine) to produce a longer protein called PTEN-Long (PTEN-L). Interestingly, the extended sequence present in PTEN-L contains cell secretion/penetration signal. Role of this non-canonical PTEN-L in diabetic renal tubular injury is not known. We show that high glucose decreases expression of PTEN-L. As a mechanism of its function, we find that reduced PTEN-L activates Akt-2, which phosphorylates and inactivate tuberin and PRAS40, resulting in activation of mTORC1 in tubular cells. Antibacterial agent acriflavine and antiviral agent ATA regulate translation from CUG codon. Acriflavine and ATA, respectively, decreased and increased expression of PTEN-L to altering Akt-2 and mTORC1 activation in the absence of change in expression of canonical PTEN. Consequently, acriflavine and ATA modulated high glucose-induced tubular cell hypertrophy and lamininγ1 expression. Importantly, expression of PTEN-L inhibited high glucose-stimulated Akt/mTORC1 activity to abrogate these processes. Since PTEN-L contains secretion/penetration signals, addition of conditioned medium containing PTEN-L blocked Akt-2/mTORC1 activity. Notably, in renal cortex of diabetic mice, we found reduced PTEN-L concomitant with Akt-2/mTORC1 activation, leading to renal hypertrophy and lamininγ1 expression. These results present first evidence for involvement of PTEN-L in diabetic kidney disease.
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Affiliation(s)
- Falguni Das
- VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA
| | | | | | - Kumar Sharma
- VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA
| | - Goutam Ghosh Choudhury
- VA Research, South Texas Veterans Health Care System, San Antonio, TX, USA; Department of Medicine, TX, USA; Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
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14
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Alajous S, Budhiraja P. New-Onset Diabetes Mellitus after Kidney Transplantation. J Clin Med 2024; 13:1928. [PMID: 38610694 PMCID: PMC11012473 DOI: 10.3390/jcm13071928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open
Abstract
New-Onset Diabetes Mellitus after Transplantation (NODAT) emerges as a prevalent complication post-kidney transplantation, with its incidence influenced by variations in NODAT definitions and follow-up periods. The condition's pathophysiology is marked by impaired insulin sensitivity and β-cell dysfunction. Significant risk factors encompass age, gender, obesity, and genetics, among others, with the use of post-transplant immunosuppressants intensifying the condition. NODAT's significant impact on patient survival and graft durability underscores the need for its prevention, early detection, and treatment. This review addresses the complexities of managing NODAT, including the challenges posed by various immunosuppressive regimens crucial for transplant success yet harmful to glucose metabolism. It discusses management strategies involving adjustments in immunosuppressive protocols, lifestyle modifications, and pharmacological interventions to minimize diabetes risk while maintaining transplant longevity. The importance of early detection and proactive, personalized intervention strategies to modify NODAT's trajectory is also emphasized, advocating for a shift towards more anticipatory post-transplant care.
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Affiliation(s)
| | - Pooja Budhiraja
- Division of Medicine, Mayo Clinic Arizona, Phoenix, AZ 85054, USA;
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15
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Sebastian-Valles F, Martínez-Alfonso J, Arranz Martin JA, Jiménez-Díaz J, Hernando Alday I, Navas-Moreno V, Armenta Joya T, Fandiño García MDM, Román Gómez GL, Lander Lobariñas LE, Martinez de Icaya P, Sampedro-Nuñez MA, Martínez-Vizacaíno V, Marazuela M. Scans per day as predictors of optimal glycemic control in people with type 1 diabetes mellitus using flash glucose monitoring: what number of scans per day should raise a red flag? Acta Diabetol 2024; 61:343-350. [PMID: 37930420 PMCID: PMC10948530 DOI: 10.1007/s00592-023-02204-x] [Citation(s) in RCA: 1] [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: 03/11/2023] [Accepted: 10/16/2023] [Indexed: 11/07/2023]
Abstract
AIMS This study aimed to determine the minimum frequency of flash glucose monitoring (FGM) scans necessary for optimal glycemic control in patients with type 1 diabetes (T1D). METHODS Data were collected from 692 patients (47.5% female, with a median age of 47.4 years) who used FGM systems daily and recorded their clinical variables and device data. RESULTS Logistic regression models showed that performing more than 12 scans per day was associated with improved T1D control (OR = 4.22, p < 0.001) and a reduction in HbA1c (7.6 vs 7.0%, 60-53 mmol/mol p < 0.001). However, those performing less than 6 scans showed no improvement in HbA1c (7.9 vs 7.8%, 63-61 mmol/mol p = 0.514). Thirteen daily scans were determined as the optimal cutoff point for predicting optimal glycemic control using a maximally selected rank algorithm. Significant reductions were observed in mean glucose (< 0.001), coefficient of variation (< 0.001), HbA1c (< 0.001), and an increase in TIR (< 0.001) in patients who performed more than 12 daily scans. CONCLUSIONS The results suggest that a higher frequency of daily scans by T1D patients using FGM systems leads to improved chronic glycemic control. The minimum recommended frequency for optimal control is 13 scans per day, and more than 6 daily scans are needed to improve HbA1c.
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Affiliation(s)
- Fernando Sebastian-Valles
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain.
| | - Julia Martínez-Alfonso
- Department of Family and Community Medicine, Hospital La Princesa/Centro de Salud Daroca, 28006, Madrid, Spain
| | - Jose Alfonso Arranz Martin
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain
| | - Jessica Jiménez-Díaz
- Department of Endocrinology and Nutrition, Hospital Universitario Severo Ochoa, 28194, Leganés, Madrid, Spain
| | - Iñigo Hernando Alday
- Department of Endocrinology and Nutrition, Hospital Universitario Basurto, 48013, Bilbao, Spain
| | - Victor Navas-Moreno
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain
| | - Teresa Armenta Joya
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain
| | | | - Gisela Liz Román Gómez
- Department of Endocrinology and Nutrition, Hospital Universitario Severo Ochoa, 28194, Leganés, Madrid, Spain
| | | | | | - Miguel Antonio Sampedro-Nuñez
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain
| | - Vicente Martínez-Vizacaíno
- Health and Social Care Research Center, Universidad de Castilla-La Mancha, 16071, Cuenca, Spain
- Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile
| | - Mónica Marazuela
- Department of Endocrinology and Nutrition, Hospital Universitario de La PrincesaInstituto de Investigación Sanitaria de La Princesa, Universidad Autónoma de Madrid, 28006, Madrid, Spain
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16
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Heurtebize MA, Faillie JL. Drug-induced hyperglycemia and diabetes. Therapie 2024; 79:221-238. [PMID: 37985310 DOI: 10.1016/j.therap.2023.09.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/14/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Drug-induced hyperglycemia and diabetes have negative and potentially serious health consequences but can often be unnoticed. METHODS We reviewed the literature searching Medline database for articles addressing drug-induced hyperglycemia and diabetes up to January 31, 2023. We also selected drugs that could induce hyperglycemia or diabetes according official data from drug information databases Thériaque and Micromedex. For each selected drug or pharmacotherapeutic class, the mechanisms of action potentially involved were investigated. For drugs considered to be at risk of hyperglycemia or diabetes, disproportionality analyses were performed using data from the international pharmacovigilance database VigiBase. In order to detect new pharmacovigilance signals, additional disproportionality analyses were carried out for drug classes with more than 100 cases reported in VigiBase, but not found in the literature or official documents. RESULTS The main drug classes found to cause hyperglycemia are glucocorticoids, HMG-coA reductase inhibitors, thiazide diuretics, beta-blockers, antipsychotics, fluoroquinolones, antiretrovirals, antineoplastic agents and immunosuppressants. The main mechanisms involved are alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Pharmacovigilance signal were found for a majority of drugs or pharmacological classes identified as being at risk of diabetes or hyperglycemia. We identified new pharmacovigilance signals with drugs not known to be at risk according to the literature or official data: phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, sodium oxybate, biphosphonates including alendronic acid, digoxin, sartans, linosipril, diltiazem, verapamil, and darbepoetin alpha. Further studies will be needed to confirm these signals. CONCLUSIONS The risks of induced hyperglycemia vary from one drug to another, and the underlying mechanisms are multiple and potentially complex. Clinicians need to be vigilant when using at-risk drugs in order to detect and manage these adverse drug reactions. However, it is to emphasize that the benefits of appropriately prescribed treatments most often outweigh their metabolic risks.
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Affiliation(s)
- Marie-Anne Heurtebize
- CHU de Montpellier, Medical Pharmacology and Toxicology Department, 34000 Montpellier, France
| | - Jean-Luc Faillie
- CHU de Montpellier, Medical Pharmacology and Toxicology Department, 34000 Montpellier, France; IDESP, Université de Montpellier, Inserm, 34295 Montpellier, France.
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17
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Uehara K, Lee WD, Stefkovich M, Biswas D, Santoleri D, Garcia Whitlock A, Quinn W, Coopersmith T, Creasy KT, Rader DJ, Sakamoto K, Rabinowitz JD, Titchenell PM. mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b. J Clin Invest 2024; 134:e173782. [PMID: 38290087 PMCID: PMC10977990 DOI: 10.1172/jci173782] [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: 07/07/2023] [Accepted: 01/26/2024] [Indexed: 02/01/2024] Open
Abstract
In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.
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Affiliation(s)
- Kahealani Uehara
- Institute for Diabetes, Obesity, and Metabolism
- Biochemistry and Molecular Biophysics Graduate Group, and
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Won Dong Lee
- Lewis Sigler Institute for Integrative Genomics
- Department of Chemistry, and
- Ludwig Institute for Cancer Research, Princeton Branch, Princeton, New Jersey, USA
| | | | - Dipsikha Biswas
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Dominic Santoleri
- Institute for Diabetes, Obesity, and Metabolism
- Biochemistry and Molecular Biophysics Graduate Group, and
| | | | | | | | - Kate Townsend Creasy
- Institute for Diabetes, Obesity, and Metabolism
- Department of Medicine, Division of Translational Medicine and Human Genetics, and
- Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Daniel J. Rader
- Institute for Diabetes, Obesity, and Metabolism
- Department of Medicine, Division of Translational Medicine and Human Genetics, and
| | - Kei Sakamoto
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Joshua D. Rabinowitz
- Lewis Sigler Institute for Integrative Genomics
- Department of Chemistry, and
- Ludwig Institute for Cancer Research, Princeton Branch, Princeton, New Jersey, USA
- Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA
| | - Paul M. Titchenell
- Institute for Diabetes, Obesity, and Metabolism
- Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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18
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Munoz Pena JM, Cusi K. Posttransplant Diabetes Mellitus: Recent Developments in Pharmacological Management of Hyperglycemia. J Clin Endocrinol Metab 2023; 109:e1-e11. [PMID: 37410930 DOI: 10.1210/clinem/dgad395] [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: 04/11/2023] [Revised: 06/20/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023]
Abstract
CONTEXT The management of solid-organ transplantation is rapidly evolving, and posttransplant diabetes mellitus (PTDM), which is increasingly common, is a barrier to transplant success, adversely impacting infection rates, allograft survival, cardiovascular disease, quality of life, and overall mortality. Currently, the management of PTDM relies primarily on intensified insulin therapy. However, emerging studies report that several noninsulin glucose-lowering agents are safe and effective in improving metabolic control and enhancing treatment adherence. More importantly, their use in PTDM can potentially transform the long-term management of these complex patients, as some glucose-lowering agents may provide benefits beyond glycemic control. For instance, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors may offer cardiorenal protection, and pioglitazone may treat nonalcoholic fatty liver disease (NAFLD). This review will focus on the pharmacological management of PTDM and the emerging evidence for noninsulin glucose-lowering agents in this population. EVIDENCE ACQUISITION Evidence from observational studies, randomized controlled trials, and meta-analyses. EVIDENCE SYNTHESIS PTDM adversely affects the outcomes of infection, organ survival, cardiovascular events, and mortality. Insulin therapy has been the drug of choice but is associated with weight gain and hypoglycemia. In contrast, noninsulin agents appear safe and may provide additional benefits, such as cardiorenal protection with SGLT-2 inhibitors and GLP-1 RA, and cardiometabolic benefits with pioglitazone, in patients undergoing solid-organ transplantation. CONCLUSIONS Optimal care of patients with PTDM requires close monitoring and the early involvement of the endocrinologist as part of a multidisciplinary team. Noninsulin glucose-lowering agents will likely play an increasing role as more long-term, controlled studies become available in this setting.
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Affiliation(s)
- Juan M Munoz Pena
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL, USA
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19
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Evans JB, Chou L, Kaeberlein M, Promislow DE, Creevy KE. Case report: Severe asymptomatic hypertriglyceridemia associated with long-term low-dose rapamycin administration in a healthy middle-aged Labrador retriever. Front Vet Sci 2023; 10:1285498. [PMID: 38094495 PMCID: PMC10716302 DOI: 10.3389/fvets.2023.1285498] [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: 08/30/2023] [Accepted: 11/02/2023] [Indexed: 02/01/2024] Open
Abstract
Rapamycin is an mTOR inhibitor that has been shown to extend the lifespan of laboratory model organisms. In humans, rapamycin is used at higher doses as an immunosuppressive medication to prevent organ rejection. Numerous adverse effects are seen with rapamycin treatment in humans, with one of the most common being dysregulation of lipid metabolism. In humans, this often manifests as mild to moderate serum lipid elevations, with a small subset developing extreme triglyceride elevations. This case report describes an eight-year-old, castrated male, clinically healthy Labrador retriever who developed severe hypertriglyceridemia associated with low-dose rapamycin administration over a six-month period. During this time, the dog was asymptomatic and displayed no other clinical abnormalities, aside from a progressive lipemia. Within 15 days of discontinuing rapamycin treatment, and with no targeted lipemic intervention, the dog's lipemia and hypertriglyceridemia completely resolved.
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Affiliation(s)
- Jeremy B. Evans
- Department of Small Animal Clinical Sciences, Texas A&M School of Veterinary Medicine & Biomedical Sciences, College Station, TX, United States
| | - Lucy Chou
- Department of Small Animal Clinical Sciences, Texas A&M School of Veterinary Medicine & Biomedical Sciences, College Station, TX, United States
| | - Matt Kaeberlein
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States
- Optispan, Inc., Seattle, WA, United States
| | - Daniel E.L. Promislow
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, United States
- Department of Biology, University of Washington, Seattle, WA, United States
| | - Kate E. Creevy
- Department of Small Animal Clinical Sciences, Texas A&M School of Veterinary Medicine & Biomedical Sciences, College Station, TX, United States
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20
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Hela F, Aguayo-Mazzucato C. Interaction between Autophagy and Senescence in Pancreatic Beta Cells. BIOLOGY 2023; 12:1205. [PMID: 37759604 PMCID: PMC10525299 DOI: 10.3390/biology12091205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/01/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023]
Abstract
Aging leads to an increase in cellular stress due to the fragility of the organism and the inability to cope with it. In this setting, there is a higher chance of developing different cardiometabolic diseases like diabetes. Cellular senescence and autophagy, both hallmarks of aging and stress-coping mechanisms, have gained increased attention for their role in the pathophysiology of diabetes. Studies show that impairing senescence dampens and even prevents diabetes while the role of autophagy is more contradictory, implying a context- and disease-stage-dependent effect. Reports show conflicting data about the effect of autophagy on senescence while the knowledge about this interaction in beta cells remains scarce. Elucidating this interaction between autophagy and senescence in pancreatic beta cells will lead to an identification of their respective roles and the extent of the effect each mechanism has on beta cells and open new horizons for developing novel therapeutic agents. To help illuminate this relationship we will review the latest findings of cellular senescence and autophagy with a special emphasis on pancreatic beta cells and diabetes.
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Affiliation(s)
| | - Cristina Aguayo-Mazzucato
- Section on Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
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21
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Granata S, Mercuri S, Troise D, Gesualdo L, Stallone G, Zaza G. mTOR-inhibitors and post-transplant diabetes mellitus: a link still debated in kidney transplantation. Front Med (Lausanne) 2023; 10:1168967. [PMID: 37250653 PMCID: PMC10213242 DOI: 10.3389/fmed.2023.1168967] [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: 02/18/2023] [Accepted: 04/25/2023] [Indexed: 05/31/2023] Open
Abstract
The mammalian target of rapamycin inhibitors (mTOR-Is, Sirolimus, and Everolimus) are immunosuppressive drugs widely employed in kidney transplantation. Their main mechanism of action includes the inhibition of a serine/threonine kinase with a pivotal role in cellular metabolism and in various eukaryotic biological functions (including proteins and lipids synthesis, autophagy, cell survival, cytoskeleton organization, lipogenesis, and gluconeogenesis). Moreover, as well described, the inhibition of the mTOR pathway may also contribute to the development of the post-transplant diabetes mellitus (PTDM), a major clinical complication that may dramatically impact allograft survival (by accelerating the development of the chronic allograft damage) and increase the risk of severe systemic comorbidities. Several factors may contribute to this condition, but the reduction of the beta-cell mass, the impairment of the insulin secretion and resistance, and the induction of glucose intolerance may play a pivotal role. However, although the results of several in vitro and in animal models, the real impact of mTOR-Is on PTDM is still debated and the entire biological machinery is poorly recognized. Therefore, to better elucidate the impact of the mTOR-Is on the risk of PTDM in kidney transplant recipients and to potentially uncover future research topics (particularly for the clinical translational research), we decided to review the available literature evidence regarding this important clinical association. In our opinion, based on the published reports, we cannot draw any conclusion and PTDM remains a challenge. However, also in this case, the administration of the lowest possible dose of mTOR-I should also be recommended.
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Affiliation(s)
- Simona Granata
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Dario Troise
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DIMEPRE-J), University of Bari, Bari, Italy
| | - Giovanni Stallone
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Zaza
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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22
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Maiese K. Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System. Biomolecules 2023; 13:816. [PMID: 37238686 PMCID: PMC10216724 DOI: 10.3390/biom13050816] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/05/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer's disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked.
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Affiliation(s)
- Kenneth Maiese
- Cellular and Molecular Signaling, New York, NY 10022, USA
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23
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Alhalabi O, Groisberg R, Zinner R, Hahn AW, Naing A, Zhang S, Tsimberidou AM, Rodon J, Fu S, Yap TA, Hong DS, Sun M, Jiang Y, Pant S, Shah AY, Zurita A, Tannir NM, Vikram R, Roszik J, Meric-Bernstam F, Subbiah V. Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies. NPJ Precis Oncol 2023; 7:37. [PMID: 37072571 PMCID: PMC10113233 DOI: 10.1038/s41698-023-00369-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 03/03/2023] [Indexed: 04/20/2023] Open
Abstract
Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.
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Affiliation(s)
- Omar Alhalabi
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roman Groisberg
- Department of Medical Oncology, Rutgers University, New Jersey, NJ, USA
| | - Ralph Zinner
- Department of Thoracic Oncology, University of Kentucky, Lexington, KY, USA
| | - Andrew W Hahn
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shizhen Zhang
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Apostolia M Tsimberidou
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jordi Rodon
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Siqing Fu
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Timothy A Yap
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - David S Hong
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ming Sun
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yunfang Jiang
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shubham Pant
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amishi Y Shah
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Amado Zurita
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nizar M Tannir
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Raghunandan Vikram
- Department of Abdominal Imaging, Division of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason Roszik
- Department of Genomic Medicine, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Vivek Subbiah
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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24
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Mohammadi-Motlagh HR, Sadeghalvad M, Yavari N, Primavera R, Soltani S, Chetty S, Ganguly A, Regmi S, Fløyel T, Kaur S, Mirza AH, Thakor AS, Pociot F, Yarani R. β Cell and Autophagy: What Do We Know? Biomolecules 2023; 13:biom13040649. [PMID: 37189396 DOI: 10.3390/biom13040649] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 05/17/2023] Open
Abstract
Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.
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Affiliation(s)
- Hamid-Reza Mohammadi-Motlagh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 67155-1616, Iran
| | - Mona Sadeghalvad
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran 1416634793, Iran
| | - Niloofar Yavari
- Department of Cellular and Molecular Medicine, The Panum Institute, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Rosita Primavera
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Setareh Soltani
- Clinical Research Development Center, Taleghani and Imam Ali Hospital, Kermanshah University of Medical Sciences, Kermanshah 67145-1673, Iran
| | - Shashank Chetty
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Abantika Ganguly
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Shobha Regmi
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Tina Fløyel
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Simranjeet Kaur
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
| | - Aashiq H Mirza
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA
| | - Avnesh S Thakor
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
| | - Flemming Pociot
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
- Institute for Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
| | - Reza Yarani
- Interventional Regenerative Innovation at Stanford (IRIS), Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94304, USA
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, 2730 Herlev, Denmark
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25
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Kale A, Rogers NM. No Time to Die-How Islets Meet Their Demise in Transplantation. Cells 2023; 12:cells12050796. [PMID: 36899932 PMCID: PMC10000424 DOI: 10.3390/cells12050796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.
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Affiliation(s)
- Atharva Kale
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Natasha M. Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Renal and Transplant Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
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26
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A mixed blessing for liver transplantation patients - Rapamycin. Hepatobiliary Pancreat Dis Int 2023; 22:14-21. [PMID: 36328894 DOI: 10.1016/j.hbpd.2022.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 10/14/2022] [Indexed: 11/04/2022]
Abstract
BACKGROUND Liver transplantation (LT) is an effective treatment option for end-stage liver disease. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, are widely used post LT. DATA SOURCES In this review, we focused on the anti-cancer activities and metabolic side effects of rapamycin after LT. The literature available on PubMed for the period of January 1999-September 2022 was reviewed. The key words were rapamycin, sirolimus, liver transplantation, hepatocellular carcinoma, diabetes, and lipid metabolism disorder. RESULTS Rapamycin has shown excellent effects and is safer than other immunosuppressive regimens. It has exhibited excellent anti-cancer activity and has the potential in preventing hepatocellular carcinoma (HCC) recurrence post LT. Rapamycin is closely related to two long-term complications after LT, diabetes and lipid metabolism disorders. CONCLUSIONS Rapamycin prevents HCC recurrence post LT in some patients, but it also induces metabolic disorders. Reasonable use of rapamycin benefits the liver recipients.
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27
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Abstract
Cellular senescence has become a subject of great interest within the ageing research field over the last 60 years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone. This chapter will also examine how senescent cell accumulation presents in these different tissues, along with their roles in disease development. Finally, there is much focus on developing treatments for senescent cell accumulation in advanced age as a method of alleviating age-related disease. We will discuss here the various senolytic and senostatic treatment approaches and their successes and limitations, and the innovative new strategies being developed to address the differing effects of cellular senescence in ageing and disease.
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Affiliation(s)
- Rebecca Reed
- Biosciences Institute, Faculty of Medical Sciences, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK
| | - Satomi Miwa
- Biosciences Institute, Faculty of Medical Sciences, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK.
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28
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Kloska SM, Pałczyński K, Marciniak T, Talaśka T, Miller M, Wysocki BJ, Davis PH, Soliman GA, Wysocki TA. Queueing theory model of mTOR complexes' impact on Akt-mediated adipocytes response to insulin. PLoS One 2022; 17:e0279573. [PMID: 36574435 PMCID: PMC9794039 DOI: 10.1371/journal.pone.0279573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 12/11/2022] [Indexed: 12/28/2022] Open
Abstract
A queueing theory based model of mTOR complexes impact on Akt-mediated cell response to insulin is presented in this paper. The model includes several aspects including the effect of insulin on the transport of glucose from the blood into the adipocytes with the participation of GLUT4, and the role of the GAPDH enzyme as a regulator of mTORC1 activity. A genetic algorithm was used to optimize the model parameters. It can be observed that mTORC1 activity is related to the amount of GLUT4 involved in glucose transport. The results show the relationship between the amount of GAPDH in the cell and mTORC1 activity. Moreover, obtained results suggest that mTORC1 inhibitors may be an effective agent in the fight against type 2 diabetes. However, these results are based on theoretical knowledge and appropriate experimental tests should be performed before making firm conclusions.
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Affiliation(s)
- Sylwester M. Kloska
- Department of Forensic Medicine, Nicolaus Copernicus University Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
- Faculty of Telecommunications, Computer Science and Electrical Engineering, Bydgoszcz University of Science and Technology, Bydgoszcz, Poland
| | - Krzysztof Pałczyński
- Faculty of Telecommunications, Computer Science and Electrical Engineering, Bydgoszcz University of Science and Technology, Bydgoszcz, Poland
| | - Tomasz Marciniak
- Faculty of Telecommunications, Computer Science and Electrical Engineering, Bydgoszcz University of Science and Technology, Bydgoszcz, Poland
| | - Tomasz Talaśka
- Faculty of Telecommunications, Computer Science and Electrical Engineering, Bydgoszcz University of Science and Technology, Bydgoszcz, Poland
| | - Marissa Miller
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Omaha, Nebraska, United States of America
| | - Beata J. Wysocki
- Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America
| | - Paul H. Davis
- Department of Biology, University of Nebraska at Omaha, Omaha, Nebraska, United States of America
| | - Ghada A. Soliman
- Department of Environmental, Occupational, and Geospatial Health Sciences, City University of New York, Graduate School of Public Health and Healthy Policy, New York, NY, United States of America
| | - Tadeusz A. Wysocki
- Faculty of Telecommunications, Computer Science and Electrical Engineering, Bydgoszcz University of Science and Technology, Bydgoszcz, Poland
- Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Omaha, Nebraska, United States of America
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29
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Lu G, Wang Y, Shi Y, Zhang Z, Huang C, He W, Wang C, Shen H. Autophagy in health and disease: From molecular mechanisms to therapeutic target. MedComm (Beijing) 2022; 3:e150. [PMID: 35845350 PMCID: PMC9271889 DOI: 10.1002/mco2.150] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/01/2022] [Accepted: 06/02/2022] [Indexed: 02/05/2023] Open
Abstract
Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over the past two decades, autophagy has been extensively studied, from the molecular mechanisms, biological functions, implications in various human diseases, to development of autophagy-related therapeutics. This review will focus on the latest development of autophagy research, covering molecular mechanisms in control of autophagosome biogenesis and autophagosome-lysosome fusion, and the upstream regulatory pathways including the AMPK and MTORC1 pathways. We will also provide a systematic discussion on the implication of autophagy in various human diseases, including cancer, neurodegenerative disorders (Alzheimer disease, Parkinson disease, Huntington's disease, and Amyotrophic lateral sclerosis), metabolic diseases (obesity and diabetes), viral infection especially SARS-Cov-2 and COVID-19, cardiovascular diseases (cardiac ischemia/reperfusion and cardiomyopathy), and aging. Finally, we will also summarize the development of pharmacological agents that have therapeutic potential for clinical applications via targeting the autophagy pathway. It is believed that decades of hard work on autophagy research is eventually to bring real and tangible benefits for improvement of human health and control of human diseases.
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Affiliation(s)
- Guang Lu
- Department of Physiology, Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Yin Shi
- Department of BiochemistryZhejiang University School of MedicineHangzhouChina
| | - Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic MedicineSichuan University and Collaborative Innovation Center for BiotherapyChengduChina
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn ResearchSouthwest HospitalArmy Medical UniversityChongqingChina
| | - Chuang Wang
- Department of Pharmacology, Provincial Key Laboratory of PathophysiologyNingbo University School of MedicineNingboZhejiangChina
| | - Han‐Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision OncologyUniversity of MacauMacauChina
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30
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Rashidmayvan M, Sahebi R, Ghayour-Mobarhan M. Long non-coding RNAs: a valuable biomarker for metabolic syndrome. Mol Genet Genomics 2022; 297:1169-1183. [PMID: 35854006 DOI: 10.1007/s00438-022-01922-1] [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: 03/27/2022] [Accepted: 06/25/2022] [Indexed: 10/17/2022]
Abstract
Long non-coding RNAs (lncRNAs) have become important regulators of gene expression because they affect a wide range of biological processes, such as cell growth, death, differentiation, and aging. More and more evidence suggests that lncRNAs play a role in maintaining metabolic homeostasis. When certain lncRNAs are out of balance, metabolic disorders like diabetes, obesity, and heart disease get worse. In this review, we talk about what we know about how lncRNAs control metabolism, with a focus on diseases caused by long-term inflammation and the characteristics of the metabolic syndrome. We looked at lncRNAs and their molecular targets in the pathogenesis of signaling pathways. We also talked about how lncRNAs are becoming more and more interesting as diagnostic and therapeutic targets for improving metabolic homeostasis.
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Affiliation(s)
- Mohammad Rashidmayvan
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Sahebi
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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31
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Pei J, Prasad M, Mohamed Helal G, El-Sherbiny M, Abdelmonem Elsherbini DM, Rajagopal P, Palanisamy CP, Veeraraghavan VP, Jayaraman S, Surapaneni KM. Beta-Sitosterol Facilitates GLUT4 Vesicle Fusion on the Plasma Membrane via the Activation of Rab/IRAP/Munc 18 Signaling Pathways in Diabetic Gastrocnemius Muscle of Adult Male Rats. Bioinorg Chem Appl 2022; 2022:7772305. [PMID: 35992048 PMCID: PMC9388314 DOI: 10.1155/2022/7772305] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 05/21/2022] [Indexed: 12/18/2022] Open
Abstract
Nutritional overload in the form of high-fat and nonglycolysis sugar intake contributes towards the accelerated creation of reactive oxygen species (ROS), hyperglycemia, and dyslipidemia. Glucose absorption and its subsequent oxidation processes in fat and muscle tissues alter as a consequence of these modifications. Insulin resistance (IR) caused glucose transporter 4 (GLUT4) translocation to encounter a challenge that manifested itself as changes in glycolytic pathways and insulin signaling. We previously found that beta (β)-sitosterol reduces IR in fat tissue via IRS-1/PI3K/Akt facilitated signaling due to its hypolipidemic and hypoglycemic activity. The intention of this research was to see whether the phytosterol β-sitosterol can aid in the translocation of GLUT4 in rats fed on high-fat diet (HFD) and sucrose by promoting Rab/IRAP/Munc 18 signaling molecules. The rats were labeled into four groups, namely control rats, HFD and sucrose-induced diabetic control rats, HFD and sucrose-induced diabetic rats given oral dose of 20 mg/kg body wt./day of β-sitosterol treatment for 30 days, and HFD and sucrose-induced diabetic animals given oral administration of 50 mg/kg body wt./day metformin for 30 days. Diabetic rats administered with β-sitosterol and normalized the titers of blood glucose, serum insulin, serum testosterone, and the status of insulin tolerance and oral glucose tolerance. In comparison with the control group, β-sitosterol effectively regulated both glycolytic and gluconeogenesis enzymes. Furthermore, qRT-PCR analysis of the mRNA levels of key regulatory genes such as SNAP23, VAMP-2, syntaxin-4, IRAP, vimentin, and SPARC revealed that β-sitosterol significantly regulated the mRNA levels of the above genes in diabetic gastrocnemius muscle. Protein expression analysis of Rab10, IRAP, vimentin, and GLUT4 demonstrated that β-sitosterol had a positive effect on these proteins, resulting in effective GLUT4 translocation in skeletal muscle. According to the findings, β-sitosterol reduced HFD and sucrose-induced IR and augmented GLUT4 translocation in gastrocnemius muscle through insulin signaling modulation via Rab/IRAP/Munc 18 and glucose metabolic enzymes. The present work is the first of its kind to show that β-sitosterol facilitates GLUT4 vesicle fusion on the plasma membrane via Rab/IRAP/Munc 18 signaling molecules in gastrocnemius muscle.
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Affiliation(s)
- JinJin Pei
- Qinba State Key Laboratory of Biological Resources and Ecological Environment, 2011 QinLing-Bashan Mountains, Bioresources Comprehensive Development C. I. C, Shaanxi Province Key Laboratory of Bio-Resources, College of Bioscience and Bioengineering, Shaanxi University of Technology, Hanzhong 723001, Shaanxi, China
| | - Monisha Prasad
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - Ghada Mohamed Helal
- Department of Medical Biochemistry, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Mohamed El-Sherbiny
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, P.O. Box 71666, Riyadh 11597, Saudi Arabia
| | - Dalia Mahmoud Abdelmonem Elsherbini
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, P.O. Box 2014, Sakaka, Saudi Arabia
- Department of Anatomy, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ponnulakshmi Rajagopal
- Central Research Laboratory, Meenakshi Academy of Higher Education and Research (Deemed to be University), Chennai 600078, India
| | - Chella Perumal Palanisamy
- State Key Laboratory of Biobased Material and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan 250353, China
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - Selvaraj Jayaraman
- Centre of Molecular Medicine and Diagnostics (COMManD), Department of Biochemistry, Saveetha Dental College & Hospital, Saveetha Institute of Medical & Technical Sciences, Saveetha University, Chennai 600077, India
| | - Krishna Mohan Surapaneni
- Departments of Biochemistry,Molecular Virology,Medical Education,Research,Clinical Skills & Simulation, Panimalar Medical College Hospital & Research Institute, Varadharajapuram, Poonamallee, Chennai 600123, India
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32
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Cuomo G, Cioffi G, Di Lorenzo A, Iannone FP, Cudemo G, Iannicelli AM, Pacileo M, D’Andrea A, Vigorito C, Iannuzzo G, Giallauria F. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients. J Clin Med 2022; 11:3247. [PMID: 35683632 PMCID: PMC9180971 DOI: 10.3390/jcm11113247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/03/2022] [Accepted: 06/04/2022] [Indexed: 01/27/2023] Open
Abstract
Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.
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Affiliation(s)
- Gianluigi Cuomo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Giuseppe Cioffi
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Di Lorenzo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Francesca Paola Iannone
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Giuseppe Cudemo
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Anna Maria Iannicelli
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Mario Pacileo
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Antonello D’Andrea
- Unit of Cardiology and Intensive Care, Umberto I Hospital, 84014 Nocera Inferiore, Italy; (M.P.); (A.D.)
| | - Carlo Vigorito
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
| | - Gabriella Iannuzzo
- Department of Clinical Medicine and Surgery, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (F.P.I.); (G.I.)
| | - Francesco Giallauria
- Department of Translational Medical Sciences, “Federico II” University of Naples, Via S. Pansini 5, 80131 Naples, Italy; (G.C.); (G.C.); (A.D.L.); (G.C.); (A.M.I.); (C.V.)
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Melick CH, Lama-Sherpa TD, Curukovic A, Jewell JL. G-Protein Coupled Receptor Signaling and Mammalian Target of Rapamycin Complex 1 Regulation. Mol Pharmacol 2022; 101:181-190. [PMID: 34965982 PMCID: PMC9092479 DOI: 10.1124/molpharm.121.000302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 11/29/2021] [Indexed: 11/30/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) senses upstream stimuli to regulate numerous cellular functions such as metabolism, growth, and autophagy. Increased activation of mTOR complex 1 (mTORC1) is typically observed in human disease and continues to be an important therapeutic target. Understanding the upstream regulators of mTORC1 will provide a crucial link in targeting hyperactivated mTORC1 in human disease. In this mini-review, we will discuss the regulation of mTORC1 by upstream stimuli, with a specific focus on G-protein coupled receptor signaling to mTORC1. SIGNIFICANCE STATEMENT: mTORC1 is a master regulator of many cellular processes and is often hyperactivated in human disease. Therefore, understanding the molecular underpinnings of G-protein coupled receptor signaling to mTORC1 will undoubtedly be beneficial for human disease.
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Affiliation(s)
- Chase H Melick
- Department of Molecular Biology, Harold C. Simmons Comprehensive Cancer, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Tshering D Lama-Sherpa
- Department of Molecular Biology, Harold C. Simmons Comprehensive Cancer, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Adna Curukovic
- Department of Molecular Biology, Harold C. Simmons Comprehensive Cancer, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jenna L Jewell
- Department of Molecular Biology, Harold C. Simmons Comprehensive Cancer, and Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Grajales D, Vázquez P, Ruíz-Rosario M, Tudurí E, Mirasierra M, Ferreira V, Hitos AB, Koller D, Zubiaur P, Cigudosa JC, Abad-Santos F, Vallejo M, Quesada I, Tirosh B, Leibowitz G, Valverde ÁM. The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice. Diabetologia 2022; 65:490-505. [PMID: 34932133 PMCID: PMC8803721 DOI: 10.1007/s00125-021-05630-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023]
Abstract
AIMS/HYPOTHESIS Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. METHODS We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5-6.0 mg kg-1 day-1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. RESULTS Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. CONCLUSIONS/INTERPRETATION Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.
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Affiliation(s)
- Diana Grajales
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Patricia Vázquez
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | | | - Eva Tudurí
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain
| | - Mercedes Mirasierra
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Vítor Ferreira
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana B Hitos
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Dora Koller
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Pablo Zubiaur
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | | | - Francisco Abad-Santos
- Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Mario Vallejo
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Iván Quesada
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain
| | - Boaz Tirosh
- The Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gil Leibowitz
- Endocrinology and Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ángela M Valverde
- Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
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Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne) 2022; 13:800995. [PMID: 35222270 PMCID: PMC8873103 DOI: 10.3389/fendo.2022.800995] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies suggest associations between diabetes mellitus and some cancers. The risk of a number of cancers appears to be increased in diabetes mellitus. On the other hand, some cancer and cancer therapies could lead to diabetes mellitus. Genetic factors, obesity, inflammation, oxidative stress, hyperglycemia, hyperinsulinemia, cancer therapies, insulin and some oral hypoglycemic drugs appear to play a role in the crosstalk between diabetes mellitus and cancers. This review summarized the associations between various types of diabetes and cancers and updated available evidence of underlying mechanisms between diabetes and cancers.
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Affiliation(s)
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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Jiang L, Qiu T, Yao X, Chen H, Yao K, Sun X, Yang G, Jiang L, Zhang C, Wang N, Zhang H, Liu X. MEHP induces pyroptosis and autophagy alternation by cathepsin B activation in INS-1 cells. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:66628-66642. [PMID: 34235687 DOI: 10.1007/s11356-021-14997-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/15/2021] [Indexed: 06/13/2023]
Abstract
Mono-(2-ethylhexyl) phthalate (MEHP) is a primary metabolite of di-(2-ethyl hexyl) phthalate (DEHP) in the organism, which is a major component of plasticizers used worldwide. Exposure to DEHP causes pancreatic beta-cell (INS-1 cells) dysfunction, which is associated with insulin resistance and type 2 diabetes. The present study shows that MEHP decreases the cell viability of INS-1 cells in a concentration-dependent manner and induces pyroptosis at 400 μM. Furthermore, the 400 μM MEHP causes increased lysosomal membrane permeability and cathepsin B (CTSB) release, resulting in NLRP3 activation and pyroptosis. Additionally, low concentration of MEHP (50-200 μM) induces upregulation of autophagy, while 400 μM MEHP reduces autophagy level in INS-1 cells via altering mTORC1 phosphorylation. Surprisingly, CTSB contributes to mTORC1 activation in INS-1 cells treated with 400 μM MEHP. Furthermore, autophagy can alleviate inflammatory response by reducing CTSB activation in MEHP-treated INS-1 cells. These results indicate that exposure to MEHP induces pyroptosis and upregulates autophagy levels in a CTSB-dependent manner, and autophagy plays an essential role in pyroptosis onset in INS-1 cells. Our findings provide a new perspective of the connection between CTSB and autophagy.
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Affiliation(s)
- Lijie Jiang
- Department of Internal Medicine, The Affiliated Zhong Shan Hospital of Dalian University, Dalian, 116001, Liaoning, People's Republic of China
| | - Tianming Qiu
- Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Xiaofeng Yao
- Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Huangben Chen
- Department of Nutrition and Food Safety, School of Public Health, College of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Kun Yao
- Department of Orthopedics, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Xiance Sun
- Department of Occupational and Environmental Health, School of Public Health, Dalian Medical University, No. 9 West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Guang Yang
- Department of Nutrition and Food Safety, School of Public Health, College of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Liping Jiang
- Preventive Medicine Laboratory, School of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Cong Zhang
- Department of Nutrition and Food Safety, School of Public Health, College of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Ningning Wang
- Department of Nutrition and Food Safety, School of Public Health, College of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China
| | - Hongying Zhang
- Department of Pathology and Forensic Medicine, Dalian Medical University, 9 West Lvshun Southern Road, Dalian, 116044, China.
| | - Xiaofang Liu
- Department of Nutrition and Food Safety, School of Public Health, College of Public Health, Dalian Medical University, No.9, West Segment of South lvshun Road, Dalian, 116044, Liaoning, People's Republic of China.
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Cheung YMM, McDonnell M, Hamnvik OPR. A targeted approach to phosphoinositide-3-kinase/Akt/mammalian target of rapamycin-induced hyperglycemia. Curr Probl Cancer 2021; 46:100776. [PMID: 34376311 DOI: 10.1016/j.currproblcancer.2021.100776] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/28/2021] [Accepted: 06/29/2021] [Indexed: 12/11/2022]
Abstract
Phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway inhibitors are a novel class of antineoplastic agent available for the treatment of various cancers. With improved cancer outcomes and survival, individuals are exposed to these antineoplastic therapies for longer periods of time and therefore, the consideration of adverse effects is of increasing importance. The PI3K/Akt/mTOR signaling pathway plays a critical role in regulating cellular processes such as growth and proliferation, but also regulates the metabolic effects of insulin such as glucose uptake and glycogen synthesis. Therefore, hyperglycemia and insulin resistance are frequently reported adverse effects. There are no recent consensus guidelines on the management of hyperglycemia secondary to PI3K/Akt/mTOR inhibitors, with the latest guidelines produced in 2012 - when many of these agents were still undergoing development. As we now have a greater understanding of the underlying mechanisms and patterns in which hyperglycemia is induced and access to an increasing array of glucose-lowering agents, an update of the previous guidelines accommodating these understandings and developments is timely. This review will provide a comprehensive summary of the current literature with regards to the incidence of hyperglycemia associated with each agent, as well as the different pathways and mechanisms in which hyperglycemia is induced. Our proposed up-to-date strategy for the specific management of PI3K/Akt/mTOR inhibitor-induced hyperglycemia will also aim to facilitate management of this complex oncological population.
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Affiliation(s)
- Yee-Ming Melody Cheung
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Department of Medicine, Endocrine Unit, Austin Hospital, The University of Melbourne, Victoria, Australia
| | - Marie McDonnell
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Ole-Petter Riksfjord Hamnvik
- Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
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Yim C, Mansell K, Hussein N, Arnason T. Current cancer therapies and their influence on glucose control. World J Diabetes 2021; 12:1010-1025. [PMID: 34326951 PMCID: PMC8311484 DOI: 10.4239/wjd.v12.i7.1010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/11/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.
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Affiliation(s)
- Carly Yim
- Department of Medicine, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Kerry Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Nassrein Hussein
- Department of Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
| | - Terra Arnason
- Departments of Anatomy and Cell Biology and Medicine, Division of Endocrinology, University of Saskatchewan, Saskatoon S7N 0W8, Saskatchewan, Canada
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Agricola K, Stires G, Krueger DA, Capal JK, Franz DN, Ritter DM. Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors. Pediatr Neurol 2021; 120:7-10. [PMID: 33962348 DOI: 10.1016/j.pediatrneurol.2021.03.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Tuberous sclerosis complex (TSC) is a genetic disorder that is manifested in multiple body systems. A mammalian target of rapamycin (mTOR) inhibitor (mTORi), either everolimus or sirolimus, is now routinely prescribed for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma and epilepsy. These medications are generally well tolerated. Side effects previously identified in well-designed clinical trials tend to be mild and readily manageable. Regulatory approvals for the treatment of TSC have expanded the use of everolimus and sirolimus clinically, enlarging clinician experience and enabling identification of potential treatment-related effects that are rarer than could be identified or recognized in previous clinical trials. METHODS The medical records of clinical patients from our TSC center who were treated with an mTORi and later developed diabetes mellitus (DM) were analyzed and compared with those who were not treated with an mTORi. Eight individuals received detailed analysis, including laboratory results, concomitant medications, and body mass indices. RESULTS Among the 1576 individuals with TSC, 4% taking an mTORi developed diabetes compared with 0.6% of those not on mTORi, showing a significant interaction between DM and mTORi (chi-square = 18.1, P < 0.001). Details of eight patients who developed DM were presented. CONCLUSIONS The long-term use of mTORi agents in TSC may contribute to a risk of diabetes. Early detection can be critical in management. Additional studies are need to further investigate a causal relationship, but clinicians should be aware of this possible association when initiating and monitoring ongoing treatment.
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Affiliation(s)
- Karen Agricola
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
| | - Gabrielle Stires
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Darcy A Krueger
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jamie K Capal
- Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - David N Franz
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - David M Ritter
- Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Neurology, University of Cincinnati College of Medicine, Cincinnati, Ohio
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Gadallah SH, Ghanem HM, Abdel-Ghaffar A, Metwaly FG, Hanafy LK, Ahmed EK. 4-Phenylbutyric acid and rapamycin improved diabetic status in high fat diet/streptozotocin-induced type 2 diabetes through activation of autophagy. Arch Physiol Biochem 2021; 127:235-244. [PMID: 31215250 DOI: 10.1080/13813455.2019.1628069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 05/31/2019] [Indexed: 10/26/2022]
Abstract
An accumulating body of evidence supports the role of autophagy in the pathophysiology of T2DM. Also, abnormal endoplasmic reticulum (ER) stress response that has been implicated as a cause of insulin resistance (IR) could also be affected by the autophagic status in β-cells. The present study was designed to investigate whether autophagy is regulated in T2DM as well as to investigate the modulatory effect of the ER stress inhibitor 4-phenylbutyric acid (4-PBA) and the autophagy inducer rapamycin (Rapa) on the autophagic and diabetic status using type 2 diabetic animal model with IR. Treatment of diabetic rats with either 4-PBA or Rapa improved significantly the states of hyperglycaemia and dyslipidaemia, increased the antioxidant capacity, reduced the levels of lipid peroxidation and ER stress and increased the autophagic flux. The obtained improvements were attributed mainly to the induction of autophagy with subsequent regulation of ER stress-oxidative activation and prevention of β-cell apoptosis.
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Affiliation(s)
- Shaimaa H Gadallah
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Hala M Ghanem
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Amany Abdel-Ghaffar
- Department of Biochemistry and Pharmacology, Research Institute of Ophthalmology, Giza, Egypt
| | - Fatma G Metwaly
- Department of Histology, Research Institute of Ophthalmology, Giza, Egypt
| | - Laila K Hanafy
- Department of Histology, Research Institute of Ophthalmology, Giza, Egypt
| | - Emad K Ahmed
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt
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Sadria M, Layton AT. Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism. Cell Commun Signal 2021; 19:57. [PMID: 34016143 PMCID: PMC8135154 DOI: 10.1186/s12964-021-00706-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/11/2021] [Indexed: 12/26/2022] Open
Abstract
Background Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals. Methods To understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+ -consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Results The model simulates the interactions among key regulators such as AKT, mTORC1, AMPK, NAD+ , and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases. Conclusions This study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.
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