|
1
|
Dhieb D, Mustafa D, Hassiba M, Alasmar M, Elsayed MH, Musa A, Zirie M, Bastaki K. Harnessing Pharmacomultiomics for Precision Medicine in Diabetes: A Comprehensive Review. Biomedicines 2025; 13:447. [PMID: 40002860 PMCID: PMC11853021 DOI: 10.3390/biomedicines13020447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2024] [Revised: 12/08/2024] [Accepted: 12/11/2024] [Indexed: 02/27/2025] Open
Abstract
Type 2 diabetes (T2D) is the fastest-growing non-communicable disease worldwide, accounting for around 90% of all diabetes cases and imposing a significant health burden globally. Due to its phenotypic heterogeneity and composite genetic underpinnings, T2D requires a precision medicine approach personalized to individual molecular profiles, thereby shifting away from the traditional "one-size-fits-all" medical methods. This review advocates for a thorough pharmacomultiomics approach to enhance precision medicine for T2D. It emphasizes personalized treatment strategies that enhance treatment efficacy while minimizing adverse effects by integrating data from genomics, proteomics, metabolomics, transcriptomics, microbiomics, and epigenomics. We summarize key findings on candidate genes impacting diabetic medication responses and explore the potential of pharmacometabolomics in predicting drug efficacy. The role of pharmacoproteomics in prognosis and discovering new therapeutic targets is discussed, along with transcriptomics' contribution to understanding T2D pathophysiology. Additionally, pharmacomicrobiomics is explored to understand gut microbiota interactions with antidiabetic drugs. Emerging evidence on utilizing epigenomic profiles in improving drug efficacy and personalized treatment is also reviewed, illustrating their implications in personalized medicine. In this paper, we discuss the integration of these layers of omics data, examining recently developed paradigms that leverage complex data to deepen our understanding of diabetes. Such integrative approaches advance precision medicine strategies to tackle the disease by better understanding its complex biology.
Collapse
Affiliation(s)
- Dhoha Dhieb
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Dana Mustafa
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Maryam Hassiba
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - May Alasmar
- Hamad Medical Corporation, Doha P.O. Box 3050, Qatar; (M.A.); (M.Z.)
| | - Mohamed Haitham Elsayed
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| | - Ameer Musa
- College of Medicine, QU Health, Qatar University, Doha P.O. Box 2713, Qatar;
| | - Mahmoud Zirie
- Hamad Medical Corporation, Doha P.O. Box 3050, Qatar; (M.A.); (M.Z.)
| | - Kholoud Bastaki
- College of Pharmacy, QU Health, Qatar University, Doha P.O. Box 2713, Qatar; (D.D.); (D.M.); (M.H.); (M.H.E.)
| |
Collapse
|
|
2
|
Sagliocchi S, Schiano E, Acampora L, Iannuzzo F, Cicatiello AG, Miro C, Nappi A, Restolfer F, Stornaiuolo M, Zarrilli S, Guerra F, Tenore GC, Dentice M, Novellino E. AbaComplex Enhances Mitochondrial Biogenesis and Adipose Tissue Browning: Implications for Obesity and Glucose Regulation. Foods 2024; 14:48. [PMID: 39796338 PMCID: PMC11720057 DOI: 10.3390/foods14010048] [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: 10/04/2024] [Revised: 12/04/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Adipose tissue, particularly white adipose tissue (WAT), plays a central role in energy storage and metabolic regulation. Excess WAT, especially visceral fat, is strongly linked to metabolic disorders such as obesity and type 2 diabetes. The browning of WAT, whereby white fat cells acquire characteristics of brown adipose tissue (BAT) with enhanced thermogenic capacity, represents a promising strategy to enhance metabolic health. In this study, we investigated the effects of chronic supplementation with an infusion based on lyophilized, thin nectarines rich in abscisic acid (ABA), named AbaComplex, on promoting browning of WAT and activating BAT in mice. Over 30 days, C57BL/6 mice were treated with the ABA-rich infusion, and various metabolic and molecular parameters were assessed. The results showed that the AbaComplex significantly increased the expression of browning markers, such as UCP1 and PGC1-α, in both visceral and subcutaneous WAT. Additionally, mitochondrial biogenesis and function were enhanced, evidenced by elevated mitochondrial DNA content and activity. The treatment also reduced the weight of WAT (both visceral and subcutaneous) and BAT and significantly improved glucose uptake in WAT via upregulation of GLUT4, suggesting enhanced insulin sensitivity. Overall, the pronounced browning effect in WAT underscores the potential of AbaComplex as a natural approach for combating obesity and improving metabolic health.
Collapse
Affiliation(s)
- Serena Sagliocchi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Elisabetta Schiano
- Inventia Biotech-Healthcare Food Research Center s.r.l., Strada Statale Sannitica KM 20.700, 81020 Caserta, Italy; (E.S.); (F.G.); (E.N.)
| | - Lucia Acampora
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Fortuna Iannuzzo
- Department of Pharmacy, University of Chieti-Pescara G. D’Annunzio, 66100 Chieti, Italy;
| | - Annunziata Gaetana Cicatiello
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Caterina Miro
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Annarita Nappi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Federica Restolfer
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Mariano Stornaiuolo
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 59, 80131 Napoli, Italy; (M.S.); (G.C.T.)
| | - Stefano Zarrilli
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Fabrizia Guerra
- Inventia Biotech-Healthcare Food Research Center s.r.l., Strada Statale Sannitica KM 20.700, 81020 Caserta, Italy; (E.S.); (F.G.); (E.N.)
| | - Gian Carlo Tenore
- Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 59, 80131 Napoli, Italy; (M.S.); (G.C.T.)
| | - Monica Dentice
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (S.S.); (L.A.); (A.G.C.); (C.M.); (A.N.); (F.R.); (S.Z.)
| | - Ettore Novellino
- Inventia Biotech-Healthcare Food Research Center s.r.l., Strada Statale Sannitica KM 20.700, 81020 Caserta, Italy; (E.S.); (F.G.); (E.N.)
- Faculty of Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
| |
Collapse
|
|
3
|
Mahendran MIMS, Gopalakrishnan V, Saravanan V, Dhamodharan R, Jothimani P, Balasubramanian M, Singh AK, Vaithianathan R. Managing drug therapy-related problems and assessment of chronic diabetic wounds. Curr Med Res Opin 2024; 40:2077-2093. [PMID: 39402701 DOI: 10.1080/03007995.2024.2414893] [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: 05/25/2024] [Revised: 09/12/2024] [Accepted: 10/07/2024] [Indexed: 11/02/2024]
Abstract
Type 2 diabetes mellitus (T2DM), responsible for most diabetes cases recorded worldwide, increases the risk of chronic wounds and amputation. Patients with T2DM appear to be more susceptible to delayed wound healing due to their treatment adherence. This review explores the specifics of polypharmacy, side effects, possible drug interactions and the importance of medication adherence for therapeutic efficacy. We discuss the effects of anti-diabetes medications on wound healing as well as the role that biofilms and microbial infections play in diabetic wounds. Inconsistent use of medications can lead to poor glycaemic control, which negatively affects the healing process of diabetic foot ulcers. Managing chronic wounds represents a substantial portion of healthcare expenditures. Biofilm-associated infections are difficult for the immune system to treat and respond inconsistently to antibiotics as these infections are slow growing and persistent. Additionally, we emphasize the critical role pharmacists play in enhancing patient adherence and optimizing diabetes treatment by offering comprehensive coverage of drugs associated with problems related to pharmacological therapy in type 2 diabetes.
Collapse
Affiliation(s)
| | - Vinoj Gopalakrishnan
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - Vaijayanthi Saravanan
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - Ramasamy Dhamodharan
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - Pradeep Jothimani
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - M Balasubramanian
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - Abhimanyu Kumar Singh
- MGM Advanced Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| | - Rajan Vaithianathan
- Department of Surgery, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Pondicherry, India
| |
Collapse
|
|
4
|
Wu Q, Jiao Y, Li J, Ma Y, Wang J, Luo M, Wang Y, Fan X, Liu C. Flavokawain B is an effective natural peroxisome proliferator-activated receptor γ-selective agonist with a strong glucose-lowering effect. Biochem Pharmacol 2024; 229:116548. [PMID: 39304103 DOI: 10.1016/j.bcp.2024.116548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 08/16/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
Rosiglitazone, a full PPARγ agonist and a classical insulin sensitizer, was once used as a powerful weapon in the treatment of T2DM. However, its applications have been restricted recently because of its multiple side effects. Here, a natural compound, flavokawain B (FKB), which was screened in our previous experiments, was investigated for its potential as a preferable insulin sensitizer because it has no or few side effects. Using the surface plasmon resonance (SPR) technique, we confirmed that FKB is a natural ligand for PPARγ with high binding affinity. In in vitro experiments, FKB significantly increased 2-NBDG uptake in HepG2 and 3T3-L1 cells, which partially stimulated PPARγ transcriptional activity. Compared with rosiglitazone, FKB had little effect on the adipose differentiation of 3T3-L1 cells, and all of these features suggest that FKB is a selective modulator of PPARγ (SPPARγM). Moreover, FKB increased the mRNA expression levels of most genes related to insulin sensitivity and glucose metabolism but had no obvious effect on those related to adipose differentiation. In vivo experiments confirmed that FKB effectively decreased abnormal fasting blood glucose and postprandial blood glucose levels and reduced glycated hemoglobin levels, similar to rosiglitazone, in HFD-fed/STZ-treated and db/db mice, two T2DM animal models, but did not cause side effects, such as weight gain or liver or kidney damage. Further investigation revealed that FKB could inhibit PPARγ-Ser273 phosphorylation, which is the key mechanism involved in improving insulin resistance. Together, FKB is a well-performing SPPARγM that exerts a powerful glucose-lowering effect without causing the same side effects as rosiglitazone, and it may have great potential for development.
Collapse
Affiliation(s)
- Qixin Wu
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yue Jiao
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jingzhe Li
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yanyan Ma
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jingyi Wang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Mingzhu Luo
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Yiting Wang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Xinrong Fan
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| | - Changzhen Liu
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
| |
Collapse
|
|
5
|
Ghareghomi S, Arghavani P, Mahdavi M, Khatibi A, García-Jiménez C, Moosavi-Movahedi AA. Hyperglycemia-driven signaling bridges between diabetes and cancer. Biochem Pharmacol 2024; 229:116450. [PMID: 39059774 DOI: 10.1016/j.bcp.2024.116450] [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: 03/29/2024] [Revised: 07/21/2024] [Accepted: 07/23/2024] [Indexed: 07/28/2024]
Abstract
Growing epidemiological evidence indicates an association between obesity, type 2 diabetes, and certain cancers, suggesting the existence of common underlying mechanisms in these diseases. Frequent hyperglycemias in type 2 diabetes promote pro-inflammatory responses and stimulate intracellular metabolic flux which rewires signaling pathways and influences the onset and advancement of different types of cancers. Here, we review the provocative impact of hyperglycemia on a subset of interconnected signalling pathways that regulate (i) cell growth and survival, (ii) metabolism adjustments, (iii) protein function modulation in response to nutrient availability (iv) and cell fate and proliferation and which are driven respectively by PI3K (Phosphoinositide 3-kinase), AMPK (AMP-activated protein kinase), O-GlcNAc (O-linked N-acetylglucosamine) and Wnt/β-catenin. Specifically, we will elaborate on their involvement in glucose metabolism, inflammation, and cell proliferation, highlighting their interplay in the pathogenesis of diabetes and cancer. Furthermore, the influence of antineoplastic and antidiabetic drugs on the unbridled cellular pathways will be examined. This review aims to inspire the next molecular studies to understand how type 2 diabetes may lead to certain cancers. This will contribute to personalized medicine and direct better prevention strategies.
Collapse
Affiliation(s)
- Somayyeh Ghareghomi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran
| | - Payam Arghavani
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Majid Mahdavi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Ali Khatibi
- Department of Biotechnology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran.
| | - Custodia García-Jiménez
- Department of Basic Health Sciences, Faculty of Health Sciences, University Rey Juan Carlos. Alcorcón, Madrid, Spain.
| | - Ali A Moosavi-Movahedi
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran; UNESCO Chair on Interdisciplinary Research in Diabetes, University of Tehran, Tehran, Iran.
| |
Collapse
|
|
6
|
Zheng H, Sechi LA, Navarese EP, Casu G, Vidili G. Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: a comprehensive review. Cardiovasc Diabetol 2024; 23:346. [PMID: 39342178 PMCID: PMC11439309 DOI: 10.1186/s12933-024-02434-5] [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: 06/12/2024] [Accepted: 09/09/2024] [Indexed: 10/01/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), poses a significant global health challenge due to its increasing prevalence and strong association with cardiovascular disease (CVD). This comprehensive review summarizes the current knowledge on the MASLD-CVD relationship, compares analysis of how different terminologies for fatty liver disease affect cardiovascular (CV) risk assessment using different diagnostic criteria, explores the pathophysiological mechanisms connecting MASLD to CVD, the influence of MASLD on traditional CV risk factors, the role of noninvasive imaging techniques and biomarkers in the assessment of CV risk in patients with MASLD, and the implications for clinical management and prevention strategies. By incorporating current research and clinical guidelines, this review provides a comprehensive overview of the complex interplay between MASLD and cardiovascular health.
Collapse
Affiliation(s)
- Haixiang Zheng
- Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy
- Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, 515041, Shantou, China
| | - Leonardo Antonio Sechi
- Department of Biomedical Sciences, University of Sassari, 07100, Sassari, Italy
- Complex Structure of Microbiology and Virology, AOU Sassari, 07100, Sassari, Italy
| | - Eliano Pio Navarese
- Clinical and Experimental Cardiology, Clinical and Interventional Cardiology, University of Sassari, Sassari, Italy
| | - Gavino Casu
- Clinical and Experimental Cardiology, Clinical and Interventional Cardiology, University of Sassari, Sassari, Italy
| | - Gianpaolo Vidili
- Department of Medicine, Surgery, and Pharmacy, University of Sassari, Azienda Ospedaliero, 07100, Sassari, Italy.
| |
Collapse
|
|
7
|
Varra FN, Varras M, Varra VK, Theodosis-Nobelos P. Molecular and pathophysiological relationship between obesity and chronic inflammation in the manifestation of metabolic dysfunctions and their inflammation‑mediating treatment options (Review). Mol Med Rep 2024; 29:95. [PMID: 38606791 PMCID: PMC11025031 DOI: 10.3892/mmr.2024.13219] [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: 10/25/2023] [Accepted: 01/17/2024] [Indexed: 04/13/2024] Open
Abstract
Obesity reaches up to epidemic proportions globally and increases the risk for a wide spectrum of co‑morbidities, including type‑2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular diseases, non‑alcoholic fatty liver disease, kidney diseases, respiratory disorders, sleep apnea, musculoskeletal disorders and osteoarthritis, subfertility, psychosocial problems and certain types of cancers. The underlying inflammatory mechanisms interconnecting obesity with metabolic dysfunction are not completely understood. Increased adiposity promotes pro‑inflammatory polarization of macrophages toward the M1 phenotype, in adipose tissue (AT), with subsequent increased production of pro‑inflammatory cytokines and adipokines, inducing therefore an overall, systemic, low‑grade inflammation, which contributes to metabolic syndrome (MetS), insulin resistance (IR) and T2DM. Targeting inflammatory mediators could be alternative therapies to treat obesity, but their safety and efficacy remains to be studied further and confirmed in future clinical trials. The present review highlights the molecular and pathophysiological mechanisms by which the chronic low‑grade inflammation in AT and the production of reactive oxygen species lead to MetS, IR and T2DM. In addition, focus is given on the role of anti‑inflammatory agents, in the resolution of chronic inflammation, through the blockade of chemotactic factors, such as monocytes chemotractant protein‑1, and/or the blockade of pro‑inflammatory mediators, such as IL‑1β, TNF‑α, visfatin, and plasminogen activator inhibitor‑1, and/or the increased synthesis of adipokines, such as adiponectin and apelin, in obesity‑associated metabolic dysfunction.
Collapse
Affiliation(s)
- Fani-Niki Varra
- Department of Pharmacy, School of Health Sciences, Frederick University, Nicosia 1036, Cyprus
- Medical School, Dimocritus University of Thrace, Alexandroupolis 68100, Greece
| | - Michail Varras
- Fourth Department of Obstetrics and Gynecology, ‘Elena Venizelou’ General Hospital, Athens 11521, Greece
| | | | | |
Collapse
|
|
8
|
Yan S, Santoro A, Niphakis MJ, Pinto AM, Jacobs CL, Ahmad R, Suciu RM, Fonslow BR, Herbst-Graham RA, Ngo N, Henry CL, Herbst DM, Saghatelian A, Kahn BB, Rosen ED. Inflammation causes insulin resistance in mice via interferon regulatory factor 3 (IRF3)-mediated reduction in FAHFA levels. Nat Commun 2024; 15:4605. [PMID: 38816388 PMCID: PMC11139994 DOI: 10.1038/s41467-024-48220-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.
Collapse
Affiliation(s)
- Shuai Yan
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA
- Harvard Medical School, 25 Shattuck St, Boston, MA, 02130, USA
| | - Anna Santoro
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA
- Harvard Medical School, 25 Shattuck St, Boston, MA, 02130, USA
| | - Micah J Niphakis
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Antonio M Pinto
- The Salk Institute for Biological Studies, 10010 N. Torey Pines Rd, La Jolla, CA, 92037-1002, USA
| | - Christopher L Jacobs
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA
- Harvard Medical School, 25 Shattuck St, Boston, MA, 02130, USA
| | - Rasheed Ahmad
- Immunology and Microbiology Department, Dasman Diabetes Institute, Jasim Mohamad Al Bahar St., Kuwait City, Kuwait
| | - Radu M Suciu
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Bryan R Fonslow
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Rachel A Herbst-Graham
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Nhi Ngo
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Cassandra L Henry
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Dylan M Herbst
- Lundbeck La Jolla Research Center Inc., 10835 Road To The Cure Dr. #250, San Diego, CA, 92121, USA
| | - Alan Saghatelian
- The Salk Institute for Biological Studies, 10010 N. Torey Pines Rd, La Jolla, CA, 92037-1002, USA
| | - Barbara B Kahn
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA
- Harvard Medical School, 25 Shattuck St, Boston, MA, 02130, USA
- Broad Institute of Harvard and MIT, 320 Charles St., Cambridge, MA, 02141, USA
| | - Evan D Rosen
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, 02215, USA.
- Harvard Medical School, 25 Shattuck St, Boston, MA, 02130, USA.
- Broad Institute of Harvard and MIT, 320 Charles St., Cambridge, MA, 02141, USA.
| |
Collapse
|
|
9
|
Zhang X, Gao Y, Tang K, Li Z, Halberstam AA, Zhou L, Perry RJ. Thiazolidinedione enhances the efficacy of anti-PD-1 monoclonal antibody in murine melanoma. Am J Physiol Endocrinol Metab 2024; 326:E341-E350. [PMID: 38294697 DOI: 10.1152/ajpendo.00346.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/10/2024] [Accepted: 01/28/2024] [Indexed: 02/01/2024]
Abstract
Several clinical studies observed a surprising beneficial effect of obesity on enhancing immunotherapy responsiveness in patients with melanoma, highlighting an as-yet insufficiently understood relationship between metabolism and immunogenicity. Here, we demonstrate that the thiazolidinedione (TZD) rosiglitazone, a drug commonly used to treat diabetes by sequestering fatty acids in metabolically inert subcutaneous adipose tissue, improved sensitivity to anti-programmed cell death protein 1 (PD-1) treatment in YUMMER1.7 tumor-bearing mice, an initially immunotherapy-sensitive murine melanoma model. We observed a transition from high to intermediate PD-1 expression in tumor-infiltrating CD8+ T cells. Moreover, TZD inhibited PD-1 expression in mouse and human T cells treated in vitro. In addition to its direct impact on immune cells, TZD also decreased circulating insulin concentrations, while insulin induced T cell exhaustion in culture. In TZD-treated mice, we observed higher fatty acid concentrations in the tumor microenvironment, with fatty acids protecting against exhaustion in culture. Together, these data are consistent with an indirect mechanism of TZD inhibiting T cell exhaustion. Finally, we analyzed imaging data from patients with melanoma before and after anti-PD-1 treatment, confirming the beneficial effect of increased subcutaneous fat on anti-PD-1 responsiveness in patients. We also found that the expression of peroxisome proliferator-activated receptor gamma (PPARγ), the canonical activator of lipid uptake and adipogenesis activated by TZD, correlated with overall survival time. Taken together, these data identify a new adjuvant to enhance immunotherapy efficacy in YUMMER1.7 melanoma mice, and discover a new metabolism-based prognostic marker in human melanoma.NEW & NOTEWORTHY Zhang et al. demonstrate that the diabetes drug rosiglitazone improves the efficacy of immunotherapy in mouse melanoma. This effect is both direct and indirect: TZD directly reduces PD-1 expression in CD8+ T cells (i.e., reduces exhaustion), and indirectly reduces exhaustion by lowering insulin levels and increasing local fat. Finally, they demonstrate that hallmarks of TZD action (such as PPARγ expression and subcutaneous fat content) correlate with improved immunotherapy efficacy in humans with melanoma.
Collapse
Affiliation(s)
- Xinyi Zhang
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Yuan Gao
- Department of Biomedical Informatics and Data Science, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Keyun Tang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Zongyu Li
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Alexandra A Halberstam
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| | - Liqun Zhou
- Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Rachel J Perry
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut, United States
| |
Collapse
|
|
10
|
Ray PK, Shabana K, Salahuddin, Kumar R. Synthetic Strategies of Thiazolidine-2,4-dione Derivatives for the Development of New Anti-diabetic Agents: Compressive Review. Curr Top Med Chem 2024; 24:885-928. [PMID: 38500288 DOI: 10.2174/0115680266284283240304071648] [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: 10/31/2023] [Revised: 02/06/2024] [Accepted: 02/13/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND Thiazolidine-2,4-dione (2,4-TZD) is a flexible pharmacophore and a privileged platform and contains a five-membered ring with a 2-oxygen atom with double bond 2,4- position and one nitrogen atom as well as sulphur containing in the heterocyclic compound. A famous electron-rich nitrogen transporter combines invigorating electronic properties with the prospective for elemental applications. Thiazolidine-2,4-dione analogues have been synthesized using a variety of methods, all of which have shown to have a strong biological effect. OBJECTIVES The study of the biological activity of Thiazolidine-2,4-dione derivatives has been a fascinating field of pharmaceutical chemistry and has many purposes. This derivative described in the literature between 1995 to 2023 was the focus of this study. Thiazolidine-2,4-diones have been discussed in terms of their introduction, general method, synthetic scheme and antidiabetic significance in the current review. CONCLUSION Thiazolidine-2,4-diones are well-known heterocyclic compounds. The synthesis of Thiazolidine-2,4-diones has been described using a variety of methods. Antidiabetic activity has been discovered in several Thiazolidine-2,4-dione derivatives, which enhance further research. The use of Thiazolidine-2,4-diones to treat antidiabetics has piqued researchers' interest in learning more about thiazolidine-2,4-diones.
Collapse
Affiliation(s)
- Pushkar Kumar Ray
- Department of Pharmacy, Harlal Institute of Management and Technology (HIMT), Plot no-8, Knowledge Park-1, Greater Noida, Uttar Pradesh, 201310, India
| | - Km Shabana
- Department of Pharmacy, Harlal Institute of Management and Technology (HIMT), Plot no-8, Knowledge Park-1, Greater Noida, Uttar Pradesh, 201310, India
| | - Salahuddin
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, Uttar Pradesh, 201306, India
| | - Rajnish Kumar
- Department of Pharmaceutical Chemistry, Noida Institute of Engineering and Technology (Pharmacy Institute), Greater Noida, Uttar Pradesh, 201306, India
| |
Collapse
|
|
11
|
Fauzi A, Thoe ES, Quan TY, Yin ACY. Insights from insulin resistance pathways: Therapeutic approaches against Alzheimer associated diabetes mellitus. J Diabetes Complications 2023; 37:108629. [PMID: 37866274 DOI: 10.1016/j.jdiacomp.2023.108629] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/03/2023] [Accepted: 10/15/2023] [Indexed: 10/24/2023]
Abstract
Alzheimer Associated Diabetes Mellitus, commonly known as Type 3 Diabetes Mellitus (T3DM) is a distinct subtype of diabetes with a pronounced association with Alzheimer's disease (AD). Insulin resistance serves as a pivotal link between these two conditions, leading to diminished insulin sensitivity, hyperglycemia, and impaired glucose uptake. The brain, a vital organ in AD context, is also significantly impacted by insulin resistance, resulting in energy deficits and neuronal damage, which are hallmark features of the neurodegenerative disorder. To pave the way for potential therapeutic interventions targeting the insulin resistance pathway, it is crucial to comprehend the intricate pathophysiology of T3DM and identify the overlapped features between diabetes and AD. This comprehensive review article aims to explore various pathway such as AMPK, PPARγ, cAMP and P13K/Akt pathway as potential target for management of T3DM. Through the analysis of these complex mechanisms, our goal is to reveal their interdependencies and support the discovery of innovative therapeutic strategies. The review extensively discusses several promising pharmaceutical candidates that have demonstrated dual drug action mechanisms, addressing both peripheral and cerebral insulin resistance observed in T3DM. These candidates hold significant promise for restoring insulin function and mitigating the detrimental effects of insulin resistance on the brain. The exploration of these therapeutic options contributes to the development of innovative interventions that alleviate the burden of T3DM and enhance patient care.
Collapse
Affiliation(s)
- Ayesha Fauzi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Ewen Se Thoe
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Tang Yin Quan
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Adeline Chia Yoke Yin
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia.
| |
Collapse
|
|
12
|
Sheikh IM, Hassan OA, Adam SM, Ali AI, Ogedegbe OJ, Tabowei G, Barbarawi A, Yussuf FM, Nor MA. Association of Pioglitazone With Major Adverse Cardiovascular Events, All-Cause Mortality, and Heart Failure Hospitalizations: A Systematic Review. Cureus 2023; 15:e46911. [PMID: 37954768 PMCID: PMC10639032 DOI: 10.7759/cureus.46911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2023] [Indexed: 11/14/2023] Open
Abstract
Modern diabetic treatment has gone beyond glycemic control, with the choice of different medications to attain therapeutic targets also affected by the risk of long-term outcomes and safety profiles. The effect of diabetes on increased morbidity and mortality and its relationship to cardiovascular outcomes and coronary artery diseases have driven recent diabetes studies toward medications that improve cardiovascular outcomes and reduce all-cause mortality. This is attained by holistically treating cardiovascular complications in type 2 diabetic patients beyond glycemic control. Moreover, both diabetes and pre-diabetes are considered risk factors for both microvascular and macrovascular cardiac events. Despite the fact that initial research acknowledged fluid retention as a safety issue in pioglitazone use, clinical trial data have not presented conclusive proof of a positive or negative impact on cardiac function. This comprehensive literature review aims to evaluate the effect of pioglitazone on all-cause mortality, hospitalizations for heart failure, and major adverse cardiovascular outcomes, including the individual outcomes of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular mortality.
Collapse
Affiliation(s)
| | - Omar A Hassan
- General Practice, Ondokuz Mayis University, Samsun, TUR
| | | | | | | | - Godfrey Tabowei
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ahmed Barbarawi
- Internal Medicine, Hennepin County Medical Center (HCMC), Minneapolis, USA
| | | | - Mohammed A Nor
- Internal Medicine, Stamford Hospital/Columbia University Vagelos College of Physicians & Surgeons, Stamford City, USA
| |
Collapse
|
|
13
|
Singla T, Muneshwar KN, Pathade AG, Yelne S. Hepatocytic Ballooning in Non-alcoholic Steatohepatitis: Bridging the Knowledge Gap and Charting Future Avenues. Cureus 2023; 15:e45884. [PMID: 37885505 PMCID: PMC10598508 DOI: 10.7759/cureus.45884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 09/22/2023] [Indexed: 10/28/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is emerging as a significant global health concern, characterized by hepatic lipid accumulation, inflammation, and hepatocellular injury. Hepatocytic ballooning, a histological feature of NASH, has gained prominence for its role in disease progression and potential as a therapeutic target. This review provides an overview of the current knowledge regarding hepatocytic ballooning in NASH, highlighting the key molecular and cellular mechanisms implicated in its development. We delve into the intricate interplay of metabolic dysregulation, oxidative stress, and lipid toxicity as drivers of hepatocytic ballooning, shedding light on the pathways responsible for its initiation and perpetuation. Furthermore, we explore the diagnostic challenges associated with hepatocytic ballooning and its significance as a prognostic indicator in NASH patients. While hepatocytic ballooning holds promise as a therapeutic target, this abstract discusses the various experimental and clinical approaches to ameliorate this histological hallmark. Potential interventions, including lifestyle modifications, pharmacological agents, and emerging therapies, are evaluated in terms of their efficacy and safety profiles. In conclusion, this review underscores the need to bridge the knowledge gap surrounding hepatocytic ballooning in NASH and emphasizes its importance in understanding disease pathogenesis and progression. By charting future research avenues and clinical strategies, we aspire to advance our comprehension of NASH and ultimately improve patient outcomes in this rapidly evolving field of hepatology.
Collapse
Affiliation(s)
- Tanvi Singla
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Komal N Muneshwar
- Community Medicine, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Aniket G Pathade
- Research and Development, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| | - Seema Yelne
- Nursing, Shalinitai Meghe College of Nursing, Datta Meghe Institute of Higher Education and Research, Wardha, IND
| |
Collapse
|
|
14
|
Bednarska K, Fecka I, Scheijen JLJM, Ahles S, Vangrieken P, Schalkwijk CG. A Citrus and Pomegranate Complex Reduces Methylglyoxal in Healthy Elderly Subjects: Secondary Analysis of a Double-Blind Randomized Cross-Over Clinical Trial. Int J Mol Sci 2023; 24:13168. [PMID: 37685975 PMCID: PMC10488144 DOI: 10.3390/ijms241713168] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/18/2023] [Accepted: 08/23/2023] [Indexed: 09/10/2023] Open
Abstract
Reactive α-dicarbonyls (α-DCs), such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are potent precursors in the formation of advanced glycation end products (AGEs). In particular, MGO and MGO-derived AGEs are thought to be involved in the development of vascular complications in diabetes. Experimental studies showed that citrus and pomegranate polyphenols can scavenge α-DCs. Therefore, the aim of this study was to evaluate the effect of a citrus and pomegranate complex (CPC) on the α-DCs plasma levels in a double-blind, placebo-controlled cross-over trial, where thirty-six elderly subjects were enrolled. They received either 500 mg of Citrus sinensis peel extract and 200 mg of Punica granatum concentrate in CPC capsules or placebo capsules for 4 weeks, with a 4-week washout period in between. For the determination of α-DCs concentrations, liquid chromatography tandem mass spectrometry was used. Following four weeks of CPC supplementation, plasma levels of MGO decreased by 9.8% (-18.7 nmol/L; 95% CI: -36.7, -0.7 nmol/L; p = 0.042). Our findings suggest that CPC supplementation may represent a promising strategy for mitigating the conditions associated with MGO involvement. This study was registered on clinicaltrials.gov as NCT03781999.
Collapse
Affiliation(s)
- Katarzyna Bednarska
- Department of Pharmacognosy, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
| | - Izabela Fecka
- Department of Pharmacognosy, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
- The Committee on Therapeutics and Pharmaceutical Sciences, The Polish Academy of Sciences, Pl. Defilad 1, 00-901 Warsaw, Poland
| | - Jean L. J. M. Scheijen
- Department of Internal Medicine, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands; (J.L.J.M.S.); (P.V.); (C.G.S.)
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Sanne Ahles
- Department of Nutrition and Movement Sciences, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, 6229 ER Maastricht, The Netherlands;
- BioActor BV, 6229 GS Maastricht, The Netherlands
| | - Philippe Vangrieken
- Department of Internal Medicine, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands; (J.L.J.M.S.); (P.V.); (C.G.S.)
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| | - Casper G. Schalkwijk
- Department of Internal Medicine, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands; (J.L.J.M.S.); (P.V.); (C.G.S.)
- CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6229 ER Maastricht, The Netherlands
| |
Collapse
|
|
15
|
Picatoste B, Cerro-Pardo I, Blanco-Colio LM, Martín-Ventura JL. Protection of diabetes in aortic abdominal aneurysm: Are antidiabetics the real effectors? Front Cardiovasc Med 2023; 10:1112430. [PMID: 37034348 PMCID: PMC10076877 DOI: 10.3389/fcvm.2023.1112430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 03/06/2023] [Indexed: 04/11/2023] Open
Abstract
Aortic aneurysms, including abdominal aortic aneurysms (AAAs), is the second most prevalent aortic disease and represents an important cause of death worldwide. AAA is a permanent dilation of the aorta on its infrarenal portion, pathologically associated with oxidative stress, proteolysis, vascular smooth muscle cell loss, immune-inflammation, and extracellular matrix remodeling and degradation. Most epidemiological studies have shown a potential protective role of diabetes mellitus (DM) on the prevalence and incidence of AAA. The effect of DM on AAA might be explained mainly by two factors: hyperglycemia [or other DM-related factors such as insulin resistance (IR)] and/or by the effect of prescribed DM drugs, which may have a direct or indirect effect on the formation and progression of AAAs. However, recent studies further support that the protective role of DM in AAA may be attributable to antidiabetic therapies (i.e.: metformin or SGLT-2 inhibitors). This review summarizes current literature on the relationship between DM and the incidence, progression, and rupture of AAAs, and discusses the potential cellular and molecular pathways that may be involved in its vascular effects. Besides, we provide a summary of current antidiabetic therapies which use could be beneficial for AAA.
Collapse
Affiliation(s)
- Belén Picatoste
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- Biomedicine Department, Alfonso X El Sabio University, Madrid, Spain
- Correspondence: Belén Picatoste ,
| | - Isabel Cerro-Pardo
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Luis M. Blanco-Colio
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- CIBERCV, Madrid, Spain
| | - Jose L. Martín-Ventura
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- CIBERCV, Madrid, Spain
- Medicine Department, Autonoma University of Madrid, Madrid, Spain
| |
Collapse
|
|
16
|
Reiser E, Lanbach J, Böttcher B, Toth B. Non-Hormonal Treatment Options for Regulation of Menstrual Cycle in Adolescents with PCOS. J Clin Med 2022; 12:jcm12010067. [PMID: 36614868 PMCID: PMC9820988 DOI: 10.3390/jcm12010067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/17/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022] Open
Abstract
Menstrual irregularities are one of the main clinical symptoms caused by polycystic ovary syndrome (PCOS). Pharmacological treatment options for non-fertility indications to restore menstrual frequency play an important role in the management of PCOS. Oral contraceptive pills are commonly prescribed for adolescents with menstrual irregularities, however, when contraindicated or poorly tolerated, further pharmacological therapy is required. This systematic literature research aims to provide an overview concerning the effects of non-hormonal pharmacological treatment options on menstrual irregularities in adolescents suffering from PCOS. A systematic literature search in PubMed, Cochrane, Embase, Bio-SISS and Web of Science was performed, including literature from January 1998 to September 2022, using specific keywords in order to find related studies. n = 265 studies were identified of which n = 164 were eligible for further evaluation. Only four placebo-controlled studies were identified, with diverging inclusion and exclusion criteria. Available data on specific non-hormonal off-label use medication primarily consisted of metformin, Glucagon-like peptide 1 receptor agonists, thiazolidinediones, anti-androgen agents (spironolactone, finasteride, flutamide) and supplements (chromium picolinate, myo-inositol). However, only a few have partly pointed out beneficial effects on improving menstrual frequency in patients diagnosed with PCOS. In summary, metformin in dosages of 1500-2550 g/day, GLP-1-analogues and supplements were effective in regulation of menstrual cycles in adolescents diagnosed with PCOS. Menstrual frequency in adolescents with PCOS is essential to prevent hypoestrogenism with long-term consequences. In this context, MET is the most effective and cost- efficient in overweight adolescent girls, also showing beneficial effects in the regulation of insulin sensitivity, especially if COCs are contraindicated or not well-tolerated. Further studies are needed to evaluate therapies in lean and normal-weight girls with PCOS.
Collapse
|
|
17
|
Theurey P, Thang C, Pirags V, Mari A, Pacini G, Bolze S, Hallakou‐Bozec S, Fouqueray P. Phase 2 trial with imeglimin in patients with Type 2 diabetes indicates effects on insulin secretion and sensitivity. Endocrinol Diabetes Metab 2022; 5:e371. [PMID: 36239048 PMCID: PMC9659655 DOI: 10.1002/edm2.371] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 08/30/2022] [Accepted: 09/04/2022] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION The aim of the present study was to evaluate the effect of 18-week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients. METHODS The study was an 18-week, double-blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h-glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity. RESULTS A total of 59 subjects were randomized, 30 receiving imeglimin and 29 receiving placebo. The study met its primary endpoint. Least squares (LS) mean difference between treatment groups (imeglimin - placebo) for AUC glucose from baseline to week 18 was -429.6 mmol/L·min (p = .001). Two-hour post-dose fasting plasma glucose was significantly decreased with LS mean differences of -1.22 mmol/L (p = .022) and HbA1c was improved with LS mean differences of -0.62% (p = .013). The AUC0-180min ratio C-peptide/glucose [LS mean differences of 0.041 nmol/mmol (p < .001)] and insulinogenic index were significantly increased by imeglimin treatment. The increase in insulin secretion was associated with an increase in beta-cell glucose sensitivity. Additionally, the insulin sensitivity indices derived from the OGTT Stumvoll (p = .001) and Matsuda (not significant) were improved in the imeglimin group vs placebo. Imeglimin was well tolerated with 26.7% of subjects presenting at least one treatment-emergent adverse event versus 58.6% of subjects in the placebo group. CONCLUSIONS Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients.
Collapse
Affiliation(s)
| | | | | | - Andrea Mari
- Institute of NeuroscienceNational Research CouncilPadovaItaly
| | | | | | | | | |
Collapse
|
|
18
|
Ballav S, Biswas B, Sahu VK, Ranjan A, Basu S. PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer. Cells 2022; 11:3215. [PMID: 36291082 PMCID: PMC9601205 DOI: 10.3390/cells11203215] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 10/03/2022] [Accepted: 10/09/2022] [Indexed: 11/16/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed.
Collapse
Affiliation(s)
- Sangeeta Ballav
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Bini Biswas
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Vishal Kumar Sahu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Amit Ranjan
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| | - Soumya Basu
- Cancer and Translational Research Centre, Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Tathawade, Pune 411033, India
| |
Collapse
|
|
19
|
Ma W, Xiao L, Liu H, Hao X. Hypoglycemic natural products with in vivo activities and their mechanisms: a review. FOOD SCIENCE AND HUMAN WELLNESS 2022. [DOI: 10.1016/j.fshw.2022.04.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
20
|
Mariadoss AVA, Sivakumar AS, Lee CH, Kim SJ. Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and molecular based treatment strategies via gene and nanotherapy. Biomed Pharmacother 2022; 151:113134. [PMID: 35617802 DOI: 10.1016/j.biopha.2022.113134] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/05/2022] [Accepted: 05/15/2022] [Indexed: 12/06/2022] Open
Abstract
Diabetes mellitus (DM) is a collection of metabolic and pathophysiological disorders manifested with high glucose levels in the blood due to the inability of β-pancreatic cells to secrete an adequate amount of insulin or insensitivity of insulin towards receptor to oxidize blood glucose. Nevertheless, the preceding definition is only applicable to people who do not have inherited or metabolic disorders. Suppose a person who has been diagnosed with Type 1 or Type 2DM sustains an injury and the treatment of the damage is complicated and prolonged. In that case, the injury is referred to as a diabetic foot ulcer (DFU). In the presence of many proliferating macrophages in the injury site for an extended period causes the damage to worsen and become a diabetic wound. In this review, the scientific information and therapeutic management of DM/DFU with nanomedicine, and other related data were collected (Web of Science and PubMed) from January 2000 to January 2022. Most of the articles revealed that standard drugs are usually prescribed along with hypoglycaemic medications. Conversely, such drugs stabilize the glucose transporters and homeostasis for a limited period, resulting in side effects such as kidney damage/failure, absorption/gastrointestinal problems, and hypoglycemic issues. In this paper, we review the current basic and clinical evidence about the potential of medicinal plants, gene therapy, chemical/green synthesized nanoparticles to improving the metabolic profile, and facilitating the DM and DFU associated complications. Preclinical studies also reported lower plasma glucose with molecular targets in DM and DFU. Research is underway to explore chemical/green synthesized nanoparticle-based medications to avoid such side effects. Hence, the present review is intended to address the current challenges, recently recognized factors responsible for DM and DFU, their pathophysiology, insulin receptors associated with DM, medications in trend, and related complications.
Collapse
Affiliation(s)
- Arokia Vijaya Anand Mariadoss
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea
| | - Allur Subramaniyan Sivakumar
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea
| | - Chang-Hun Lee
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Sung Jae Kim
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea.
| |
Collapse
|
|
21
|
Hosseini Dastgerdi A, Ghanbari Rad M, Soltani N. The Therapeutic Effects of Magnesium in Insulin Secretion and Insulin Resistance. Adv Biomed Res 2022; 11:54. [PMID: 35982863 PMCID: PMC9379913 DOI: 10.4103/abr.abr_366_21] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 01/26/2022] [Accepted: 02/08/2022] [Indexed: 11/09/2022] Open
Abstract
Insulin resistance (IR) is a chronic pathological condition that is related to reduce the rates of glucose uptake, especially in the liver, muscle, and adipose tissue as target tissues. Metabolic syndrome and type 2 diabetes mellitus can occur following progression of the disease. The majority of prior research has applied that some cations such as magnesium (Mg2+) have important physiological role in insulin metabolism. Mg2+ is the fourth most abundant mineral in the human body that gets involved as a cofactor of various enzymes in several metabolic events, such as carbohydrate oxidation, and it has a fundamental role in glucose transporting mechanism of the cell membrane. This cation has numerous duties in the human body such as regulation of insulin secretion in pancreatic beta-cells and phosphorylation of the insulin receptors in target cells and also gets involved in other downstream signal kinases as intracellular cation. On this basis, intracellular Mg2+ balancing is vital for adequate carbohydrate metabolism. This paper summarizes the present knowledge about the therapeutic effects of Mg2+ in reducing IR in liver, muscle, and pancreases with different mechanisms. For this, the search was performed in Google Scholar, PubMed, Scopus, and Web of Science by insulin resistance, skeletal muscle, liver, pancreases, magnesium, Mg2+, and inflammation keywords.
Collapse
Affiliation(s)
| | - Mahtab Ghanbari Rad
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nepton Soltani
- Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran,Address for correspondence: Prof. Nepton Soltani, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. E-mail:
| |
Collapse
|
|
22
|
Kim DH, Min SG, Kim HM, Kang HR, Choi JH, Lee HJ, Kim KR, Chung SW, Yoon JP. Comparison of the Characteristics of Rotator Cuff Tissue in a Diabetic Rat Model. Orthopedics 2022; 45:e154-e161. [PMID: 35112964 DOI: 10.3928/01477447-20220128-08] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This study evaluated the biomechanical and histologic characteristics of the rotator cuff tendon and muscle tissue with rat models with diabetes mellitus (DM) (group 1) and 30 male rats without DM (group 2). We conducted a time zero study without any additional procedures or external variables at 9 weeks after induction of the diabetic rat model. Thereafter, quantitative evaluation of advanced glycation end products (AGEs) was accomplished via enzyme-linked immunosorbent assay and immunohistochemistry (IHC). Fatty infiltration was investigated with Oil Red O staining, and the peroxisome proliferator activated receptor-gamma (PPAR-gamma) value was studied with IHC. Grossly, the supraspinatus tendons of the group 1 rats were more friable and discolored (yellowish) than those of group 2. In the biomechanical analysis, group 1 rats showed significantly inferior ultimate failure load (P=.001) and ultimate stress (P=.02). Group 1 was significantly inferior to group 2 in terms of total histologic scoring (P<.001). Mean AGE levels were significantly higher in group 1 (P<.001), as determined by IHC. In evaluating fatty infiltration, the degree of Oil Red O staining was significantly higher in group 1 (P<.001), but there was no significant difference in PPAR-gamma value between the 2 groups (P=.14). The intact rotator cuffs of rats with DM were associated with inferior biomechanics in association with AGE accumulation and increased fatty infiltration, as confirmed by histologic examination The hyperglycemic state caused by DM is associated with rotator cuff tendon degeneration. [Orthopedics. 2022;45(3):e154-e161.].
Collapse
|
|
23
|
Dutra LA, Lacerda MG, Destro Inácio M, Martins JW, Lopes Silva AC, Bento da Silva P, Chorilli M, Amato AA, Baviera AM, Passarelli M, Guido RV, Dos Santos JL. Discovery of (E)-4-styrylphenoxy-propanamide: A dual PPARα/γ partial agonist that regulates high-density lipoprotein-cholesterol levels, modulates adipogenesis, and improves glucose tolerance in diet-induced obese mice. Bioorg Chem 2022; 120:105600. [DOI: 10.1016/j.bioorg.2022.105600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/28/2021] [Accepted: 01/04/2022] [Indexed: 11/02/2022]
|
|
24
|
In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents. PPAR Res 2022; 2021:5100531. [PMID: 35003235 PMCID: PMC8741387 DOI: 10.1155/2021/5100531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/30/2021] [Accepted: 12/06/2021] [Indexed: 12/19/2022] Open
Abstract
Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups (n = 7): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.
Collapse
|
|
25
|
Tavakoli-Rouzbehani OM, Faghfouri AH, Anbari M, Papi S, Shojaei FS, Ghaffari M, Alizadeh M. The effects of Cuminum cyminum on glycemic parameters: A systematic review and meta-analysis of controlled clinical trials. JOURNAL OF ETHNOPHARMACOLOGY 2021; 281:114510. [PMID: 34371114 DOI: 10.1016/j.jep.2021.114510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 07/23/2021] [Accepted: 08/06/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cuminum Cyminum (CC) is a traditional herbal medicine using as an antiseptic, anti-carcinogenic, anti-mutagenic, anti-cancer, anti-hypertensive, anti-inflammatory, and antioxidant. Recently hypoglycemic characteristics of CC have been indicated. AIM OF THE STUDY We intended to conduct a meta-analysis on the effect of CC supplementation on glycemic parameters in patients with different chronic diseases. MATERIALS AND METHODS PubMed, Embase, Web of Science, and Scopus were searched until May 2021. Random effect model was conducted to perform the meta-analysis. Source of heterogeneity was explored using the meta-regression and subgroup analyses. The Cochrane Collaboration's tool was used to assess the quality of studies. The GRADE approach was used to assess the quality of evidence. RESULTS Findings of eight studies showed that CC supplementation reduced FBS (SMD = -1.4 mg/dl; 95 % CI: -2.29, -0.51; P = 0.002), HbA1c (SMD = -1.71 %; 95 % CI: -3.24, -0.18; P = 0.028), and HOMA-β (SMD = 0.46; 95 % CI: -0.62, 1.55; P = 0.404) significantly. Also, CC increased QUICKI level (SMD = 0.89; 95 % CI: 0.37, 1.4; P = 0.001. However, no significant effect of CC was observed on insulin (SMD = -0.70 μIU/dl; 95 % CI: -1.84, 0.45; P = 0.234) and HOMA-IR (SMD = 0.46; 95 % CI: -0.62, 1.55; P = 0.404). CONCLUSION CC had an improving effect on FBS, HbA1C, HOMA-B, and QUICKI. The effect of CC on amending HOMA-IR was significant after sensitivity analysis. However, the insulin level was not changed significantly.
Collapse
Affiliation(s)
| | - Amir Hossein Faghfouri
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Community Nutrition, School of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Maryam Anbari
- Department of Clinical Nutrition, School of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Shahab Papi
- Department of Public Health, Faculty of Health, Social Determinants of Health Research Center, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Farid Salimi Shojaei
- Department of Medical Sciences, Marand Branch, Islamic Azad University, Marand, Iran
| | - Mehdi Ghaffari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Alizadeh
- Department of Clinical Nutrition, School of Nutrition and Food Science, Tabriz University of Medical Sciences, Tabriz, Iran.
| |
Collapse
|
|
26
|
Habibi-Khorassani SM, Shahraki M, Talaiefar S, Ghodsi F. Ionic strength effect on the kinetics and mechanism of N-vinyl compound formation in the presence of heterocyclic biological base: empirical and theoretical approaches. Mol Phys 2021. [DOI: 10.1080/00268976.2021.1957171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
| | - Mehdi Shahraki
- Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
| | - Sadegh Talaiefar
- Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
| | - Fatemeh Ghodsi
- Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
| |
Collapse
|
|
27
|
Venkatachalapathy P, Padhilahouse S, Sellappan M, Subramanian T, Kurian SJ, Miraj SS, Rao M, Raut AA, Kanwar RK, Singh J, Khadanga S, Mondithoka S, Munisamy M. Pharmacogenomics and Personalized Medicine in Type 2 Diabetes Mellitus: Potential Implications for Clinical Practice. Pharmgenomics Pers Med 2021; 14:1441-1455. [PMID: 34803393 PMCID: PMC8598203 DOI: 10.2147/pgpm.s329787] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 10/04/2021] [Indexed: 12/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and is rising in incidence with widespread prevalence. Multiple gene variants are associated with glucose homeostasis, complex T2DM pathogenesis, and its complications. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Pharmacogenomics has made precision medicine possible by allowing for individualized drug therapy based on a patient's genetic and genomic information. T2DM is treated with various classes of oral hypoglycemic agents, such as biguanides, sulfonylureas, thiazolidinediones, meglitinides, DPP4 inhibitors, SGLT2 inhibitors, α-glucosidase inhibitors, and GLP1 analogues, which exhibit various pharmacogenetic variants. Although genomic interventions in monogenic diabetes have been implemented in clinical practice, they are still in the early stages for complex polygenic disorders, such as T2DM. Precision DM medicine has the potential to be effective in personalized therapy for those suffering from various forms of DM, such as T2DM. With recent developments in genetic techniques, the application of candidate-gene studies, large-scale genotyping investigations, genome-wide association studies, and "multiomics" studies has begun to produce results that may lead to changes in clinical practice. Enhanced knowledge of the genetic architecture of T2DM presents a bigger translational potential. This review summarizes the genetics and pathophysiology of T2DM, candidate-gene approaches, genome-wide association studies, personalized medicine, clinical relevance of pharmacogenetic variants associated with oral hypoglycemic agents, and paths toward personalized diabetology.
Collapse
Affiliation(s)
| | - Sruthi Padhilahouse
- Department of Pharmacy Practice, Karpagam College of Pharmacy, Coimbatore, Tamilnadu, India
| | - Mohan Sellappan
- Department of Pharmacy Practice, Karpagam College of Pharmacy, Coimbatore, Tamilnadu, India
| | | | - Shilia Jacob Kurian
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sonal Sekhar Miraj
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Mahadev Rao
- Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Ashwin Ashok Raut
- Translational Medicine Centre, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Rupinder Kaur Kanwar
- Translational Medicine Centre, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Jitendra Singh
- Translational Medicine Centre, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Sagar Khadanga
- Department of General Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Sukumar Mondithoka
- Department of General Medicine, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| | - Murali Munisamy
- Translational Medicine Centre, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
| |
Collapse
|
|
28
|
Shah N, Abdalla MA, Deshmukh H, Sathyapalan T. Therapeutics for type-2 diabetes mellitus: a glance at the recent inclusions and novel agents under development for use in clinical practice. Ther Adv Endocrinol Metab 2021; 12:20420188211042145. [PMID: 34589201 PMCID: PMC8474306 DOI: 10.1177/20420188211042145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 08/06/2021] [Indexed: 12/18/2022] Open
Abstract
Diabetes mellitus (DM) is a chronic, progressive, and multifaceted illness resulting in significant physical and psychological detriment to patients. As of 2019, 463 million people are estimated to be living with DM worldwide, out of which 90% have type-2 diabetes mellitus (T2DM). Over the years, significant progress has been made in identifying the risk factors for developing T2DM, understanding its pathophysiology and uncovering various metabolic pathways implicated in the disease process. This has culminated in the implementation of robust prevention programmes and the development of effective pharmacological agents, which have had a favourable impact on the management of T2DM in recent times. Despite these advances, the incidence and prevalence of T2DM continue to rise. Continuing research in improving efficacy, potency, delivery and reducing the adverse effect profile of currently available formulations is required to keep pace with this growing health challenge. Moreover, new metabolic pathways need to be targeted to produce novel pharmacotherapy to restore glucose homeostasis and address metabolic sequelae in patients with T2DM. We searched PubMed, MEDLINE, and Google Scholar databases for recently included agents and novel medication under development for treatment of T2DM. We discuss the pathophysiology of T2DM and review how the emerging anti-diabetic agents target the metabolic pathways involved. We also look at some of the limiting factors to developing new medication and the introduction of unique methods, including facilitating drug delivery to bypass some of these obstacles. However, despite the advances in the therapeutic options for the treatment of T2DM in recent years, the industry still lacks a curative agent.
Collapse
Affiliation(s)
- Najeeb Shah
- Hull University Teaching Hospitals NHS Trust,
Hull, UK
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Brocklehurst
Building, 220-236 Anlaby Road, Hull, HU3 2RW, UK
| | - Mohammed Altigani Abdalla
- Department of Academic Diabetes, Endocrinology
& Metabolism, Hull York Medical School, University of Hull, Hull,
UK
| | - Harshal Deshmukh
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
| | - Thozhukat Sathyapalan
- University Teaching Hospitals NHS Trust and
Department of Academic Diabetes, Endocrinology & Metabolism, Hull York
Medical School, University of Hull, Hull, UK
| |
Collapse
|
|
29
|
Yang BR, Cha SH, Lee KE, Kim JW, Lee J, Shin KH. Effect of dipeptidyl peptidase IV inhibitors, thiazolidinedione, and sulfonylurea on osteoporosis in patients with type 2 diabetes: population-based cohort study. Osteoporos Int 2021; 32:1705-1712. [PMID: 33594487 DOI: 10.1007/s00198-020-05801-6] [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: 06/11/2020] [Accepted: 12/15/2020] [Indexed: 12/01/2022]
Abstract
UNLABELLED The population-based cohort study used the Korean National Health Insurance claims database to evaluate the effect of anti-diabetic drugs on osteoporosis. The use of DPP-IV inhibitors does not increase the risk of osteoporosis compared with the use of sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis. PURPOSE The current study aimed to evaluate the effect of dipeptidyl peptidase IV inhibitors (DPP-IVi), thiazolidinedione (TZD), and sulfonylurea (SU) on osteoporosis in patients with type 2 diabetes. METHODS A population-based cohort study was conducted in the Republic of Korea using the Korean National Health Insurance claims database. Data from 2012 to 2017 for patients of 50-99 years of age who were prescribed DPP-IVi, TZD, or SU during 2013-2015 were extracted from the database. Based on pre-defined criteria, a total of 381,404 patients were analyzed after inverse probability of treatment weighting. The association between the study drugs and osteoporosis was estimated using Cox proportional hazards models. Data of 220,166 patients who were prescribed DPP-IVi, 18,630 who were prescribed TZD, and 142,608 patients who were prescribed SU were set. RESULTS In the multivariate-adjusted analysis, the hazard ratio (HR) of osteoporosis in the DPP-IVi group was not significantly different from that of the SU group (HR: 0.97; 95% confidence interval (CI) 0.94-1.00), whereas the HR of osteoporosis in the TZD group was higher (HR: 1.13; 95% CI 1.06-1.20). In the subgroup analysis, the HRs of osteoporosis were higher with pioglitazone (HR: 1.14; 95% CI 1.06-1.23) in the TZD group and with glibenclamides (HR: 1.39; 95% CI 1.09-1.77) in the SU group, whereas drugs with lower HR in the DPP-IVi group were saxagliptin (HR: 0.93; 95% CI 0.87-0.99) and sitagliptin (HR: 0.93; 95% CI 0.89-0.97). CONCLUSION DPP-IV inhibitors do not increase the risk of osteoporosis compared with sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis.
Collapse
Affiliation(s)
- B R Yang
- College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea
| | - S H Cha
- Department of Statistics, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - K E Lee
- Department of Statistics, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - J W Kim
- Department of Family Medicine, Daegu Health College Hospital, Daegu, Republic of Korea
| | - J Lee
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea
| | - K-H Shin
- College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu, 41566, Republic of Korea.
| |
Collapse
|
|
30
|
Phillips J, Chen JHC, Ooi E, Prunster J, Lim WH. Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:731574. [PMID: 36994340 PMCID: PMC10012134 DOI: 10.3389/fcdhc.2021.731574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.
Collapse
Affiliation(s)
- Jessica Phillips
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- *Correspondence: Jessica Phillips,
| | - Jenny H. C. Chen
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- Depatment of Nephrology, Wollongong Hospital, Wollongong, NSW, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns, QLD, Australia
| | - Wai H. Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Medical School, University of Western Australia, Perth, WA, Australia
| |
Collapse
|
|
31
|
Srivastava A, Palaia T, Hall C, Stevenson M, Lee J, Ragolia L. Lipocalin-type Prostaglandin D2 Synthase appears to function as a Novel Adipokine Preventing Adipose Dysfunction in response to a High Fat Diet. Prostaglandins Other Lipid Mediat 2021; 157:106585. [PMID: 34371198 DOI: 10.1016/j.prostaglandins.2021.106585] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/24/2021] [Accepted: 08/03/2021] [Indexed: 12/29/2022]
Abstract
Adipose dysfunction is the primary defect in obesity that contributes to the development of dyslipidemia, insulin resistance, cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFLD) and some cancers. Previously, we demonstrated the development of NAFLD in lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice regardless of diet. In the present study, we examined the role of L-PGDS in adipose in response to a high fat diet. We observed decreased expression of L-PGDS in adipose tissue and concomitant lower plasma levels in a dietary model of obesity as well as in insulin resistant 3T3-L1 adipocytes. We show reduced adiponectin expression and phosphorylation of AMPK in white adipose tissue of L-PGDS KO mice after 14 weeks on a high fat diet as compared to control C57BL/6 mice. We also observe an increased fat content in L-PGDS KO mice as demonstrated by adipocyte hypertrophy and increased expression of lipogenenic genes. We confirmed our in vivo findings in in vitro 3T3-L1 adipocytes, using an enzymatic inhibitor of L-PGDS (AT56). Rosiglitazone treatment drastically increased L-PGDS expression in insulin resistant 3T3-L1 adipocytes and increased adiponectin expression and AMPK phosphorylation in AT56 treated 3T3-L1 adipocytes. We conclude that the absence of L-PGDS has a deleterious effect on adipose tissue functioning, which further reduces insulin sensitivity in adipose tissue. Consequently, we propose L-PGDS appears to function as a potential member of the adipokine secretome involved in the regulation of the obesity-associated metabolic syndrome.
Collapse
Affiliation(s)
- Ankita Srivastava
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States
| | - Thomas Palaia
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States; Department of Foundations of Medicine, NYU Long Island School of Medicine, 101 Mineola Blvd. Suite 4-003, Mineola, NY, 11501, United States
| | - Christopher Hall
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States
| | - Matthew Stevenson
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States
| | - Jenny Lee
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States
| | - Louis Ragolia
- Department of Biomedical research, NYU Langone Hospital, Long Island, United States; Department of Foundations of Medicine, NYU Long Island School of Medicine, 101 Mineola Blvd. Suite 4-003, Mineola, NY, 11501, United States.
| |
Collapse
|
|
32
|
Stopponi S, Fotio Y, Cifani C, Li H, Haass-Koffler CL, Cannella N, Demopulos G, Gaitanaris G, Ciccocioppo R. Andrographis paniculata and Its Main Bioactive Ingredient Andrographolide Decrease Alcohol Drinking and Seeking in Rats Through Activation of Nuclear PPARγ Pathway. Alcohol Alcohol 2021; 56:240-249. [PMID: 33401299 DOI: 10.1093/alcalc/agaa136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND AIMS Andrographis paniculata is an annual herbaceous plant which belongs to the Acanthaceae family. Extracts from this plant have shown hepatoprotective, anti-inflammatory and antidiabetic properties, at least in part, through activation of the nuclear receptor Peroxisome Proliferator-Activated Receptor-gamma (PPAR γ). Recent evidence has demonstrated that activation of PPARγ reduces alcohol drinking and seeking in Marchigian Sardinian (msP) alcohol-preferring rats. METHODS The present study evaluated whether A. paniculata reduces alcohol drinking and relapse in msP rats by activating PPARγ. RESULTS Oral administration of an A. paniculata dried extract (0, 15, 150 mg/kg) lowered voluntary alcohol consumption in a dose-dependent manner and achieved ~65% reduction at the dose of 450 mg/kg. Water and food consumption were not affected by the treatment. Administration of Andrographolide (5 and 10 mg/kg), the main active component of A. paniculata, also reduced alcohol drinking. This effect was suppressed by the selective PPARγ antagonist GW9662. Subsequently, we showed that oral administration of A. paniculata (0, 150, 450 mg/kg) prevented yohimbine- but not cues-induced reinstatement of alcohol seeking. CONCLUSIONS Results point to A. paniculata-mediated PPARγactivation as a possible therapeutic strategy to treat alcohol use disorder.
Collapse
Affiliation(s)
- Serena Stopponi
- School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
| | - Yannick Fotio
- School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy.,Department of Anatomy and Neurobiology, School of Medicine, University of California, 807 Health Science Road, 92617 Irvine, USA
| | - Carlo Cifani
- School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
| | - Hongwu Li
- College of Chemical Engineering, Changchun University of Technology, 2055 Yan An Road, Chao Yang District, 130021 Changchun, China
| | - Carolina L Haass-Koffler
- Center Alcohol and Addiction Studies, Department Psychiatry and Human Behavior Department Behavioral and Social Sciences Brow University 121 S. Main Street, Providence, RI 02931, USA
| | - Nazzareno Cannella
- School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
| | - Gregory Demopulos
- Center Alcohol and Addiction Studies, Department Psychiatry and Human Behavior Department Behavioral and Social Sciences Brow University 121 S. Main Street, Providence, RI 02931, USA
| | - George Gaitanaris
- Center Alcohol and Addiction Studies, Department Psychiatry and Human Behavior Department Behavioral and Social Sciences Brow University 121 S. Main Street, Providence, RI 02931, USA.,Omeros Corporation, 201 Elliot Avenue West, Seattle, WA 98119, USA
| | - Roberto Ciccocioppo
- School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy
| |
Collapse
|
|
33
|
Saini AK, Saini R, Singh S. Autosomal dominant polycystic kidney disease and pioglitazone for its therapy: a comprehensive review with an emphasis on the molecular pathogenesis and pharmacological aspects. Mol Med 2020; 26:128. [PMID: 33308138 PMCID: PMC7731470 DOI: 10.1186/s10020-020-00246-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022] Open
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited chronic kidney disorder (CKD) that is characterized by the development of numerous fluid-filled cysts in kidneys. It is caused either due to the mutations in the PKD1 or PKD2 gene that encodes polycystin-1 and polycystin-2, respectively. This condition progresses into end-stage renal disorder if the renal or extra-renal clinical manifestations remain untreated. Several clinical trials with a variety of drugs have failed, and the only Food and Drugs Administration (FDA) approved drug to treat ADPKD to date is tolvaptan that works by antagonizing the vasopressin-2 receptor (V2R). The pathology of ADPKD is complex and involves the malfunction of different signaling pathways like cAMP, Hedgehog, and MAPK/ERK pathway owing to the mutated product that is polycystin-1 or 2. A measured yet substantial number of preclinical studies have found pioglitazone to decrease the cystic burden and improve the renal function in ADPKD. The peroxisome proliferator-activated receptor-gamma is found on the epithelial cells of renal collecting tubule and when it gets agonized by pioglitazone, confers efficacy in ADPKD treatment through multiple mechanisms. There is only one clinical trial (ongoing) wherein it is being assessed for its benefits and risk in patients with ADPKD, and is expected to get approval from the regulatory body owing to its promising therapeutic effects. This article would encompass the updated information on the epidemiology, pathophysiology of ADPKD, different mechanisms of action of pioglitazone in the treatment of ADPKD with preclinical and clinical shreds of evidence, and related safety updates.
Collapse
Affiliation(s)
- Aryendu Kumar Saini
- Department of Pharmacy, Chaudhary Sughar Singh College of Pharmacy, Etawah, Uttar Pradesh, India.
| | - Rakesh Saini
- Department of Pharmacy, Chaudhary Sughar Singh College of Pharmacy, Etawah, Uttar Pradesh, India
| | - Shubham Singh
- Department of Pharmacy, Shri Ram Lakhan Tiwari College of Pharmacy, Etawah, Uttar Pradesh, India
| |
Collapse
|
|
34
|
Chen HF, Chang YH, Lo HJ, Isfandiari MA, Martini S, Hou WH, Li CY. Incidence of idiopathic cardiomyopathy in patients with type 2 diabetes in Taiwan: age, sex, and urbanization status-stratified analysis. Cardiovasc Diabetol 2020; 19:177. [PMID: 33054769 PMCID: PMC7558694 DOI: 10.1186/s12933-020-01144-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 09/27/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The epidemiology of diabetes and idiopathic cardiomyopathy have limited data. We investigated the overall and the age-, sex-, and urbanization-specific incidence and relative hazard of idiopathic cardiomyopathy in association with type 2 diabetes and various anti-diabetic medications used in Taiwan. METHODS A total of 474,268 patients with type 2 diabetes were identified from ambulatory care and inpatient claims in 2007-2009 from Taiwan's National Health Insurance (NHI) database. We randomly selected 474,266 age-, sex-, and diagnosis date-matched controls from the registry of NHI beneficiaries. All study subjects were linked to ambulatory care and inpatient claims (up to the end of 2016) to identify the possible diagnosis of idiopathic cardiomyopathy. The person-year approach with Poisson assumption was used to estimate the incidence, and Cox proportional hazard regression model with Fine and Gray's method was used to estimate the relative hazards of idiopathic cardiomyopathy in relation to type 2 diabetes. RESULTS The overall incidence of idiopathic cardiomyopathy for men and women patients, respectively, was 3.83 and 2.94 per 10,000 person-years, which were higher than the corresponding men and women controls (2.00 and 1.34 per 10,000 person-years). Compared with the control group, patients with type 2 diabetes were significantly associated with an increased hazard of idiopathic cardiomyopathy (adjusted hazard ratio [aHR]: 1.60, 95% confidence interval [CI]: 1.45-1.77] in all age and sex stratifications except in those men aged > 64 years. Patients with type 2 diabetes aged < 45 years confronted the greatest increase in the hazard of idiopathic cardiomyopathy, with an aHR of 3.35 (95% CI 2.21-5.06) and 3.48 (95% CI 1.60-7.56) for men and women, respectively. The usage of some anti-diabetic medications revealed lower risks of idiopathic cardiomyopathy. CONCLUSIONS In Taiwan, diabetes increased the risk of idiopathic cardiomyopathy in both sexes and in all age groups, except in men aged > 64 years. Younger patients were vulnerable to have higher HRs of idiopathic cardiomyopathy. Some anti-diabetic medications may reduce the risks of cardiomyopathy.
Collapse
Affiliation(s)
- Hua-Fen Chen
- Department of Endocrinology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
- School of Medicine and Department of Public Health, College of Medicine, Fujen Catholic University, New Taipei City, Taiwan
| | - Ya-Hui Chang
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hsien-Jung Lo
- Department of Cardiology, Cardiovascular Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | | | - Santi Martini
- Department of Epidemiology, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia
| | - Wen-Hsuan Hou
- Department of Physical Medicine and Rehabilitation, Taipei Medical University Hospital, Taipei, Taiwan
- Master Program in Long-Term Care, College of Nursing, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chung-Yi Li
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Department of Epidemiology, Faculty of Public Health, Universitas Airlangga, Surabaya, Indonesia.
- Department of Public Health, College of Public Health, China Medical University, Taichung City, Taiwan.
- Department of Healthcare Administration, College of Medical and Health Science, Asia University, Taichung City, Taiwan.
| |
Collapse
|
|
35
|
Unearthing novel thiazolidinone building blocks as carboxylic acid bioisosteres. Future Med Chem 2020; 12:1855-1864. [PMID: 33012189 DOI: 10.4155/fmc-2020-0192] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Aim: Thiazolidinones were prepared as building blocks for the replacement of carboxylic acids. Materials & methods: Chemical syntheses of thiazolidinones were developed. In addition, the drug-likeness of the target compounds was evaluated in silico. Results: The prepared compounds included the novel structure 4; 5-(3-Iodophenylmethylene)-2,4-thiazolidinedione. Conclusion: Exploration of the methods required to synthesize thiazolidinone building blocks was completed. This work allows future generation of bioisosteric analogs of drugs.
Collapse
|
|
36
|
Piqué DG, Greally JM, Mar JC. Identification of a novel subgroup of endometrial cancer patients with loss of thyroid hormone receptor beta expression and improved survival. BMC Cancer 2020; 20:857. [PMID: 32894083 PMCID: PMC7487950 DOI: 10.1186/s12885-020-07325-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 08/20/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Endometrial cancer (EC) is the most common gynecologic cancer in women, and the incidence of EC has increased by about 1% per year in the U. S over the last 10 years. Although 5-year survival rates for early-stage EC are around 80%, certain subtypes of EC that lose nuclear hormone receptor (NHR) expression are associated with poor survival rates. For example, estrogen receptor (ER)-negative EC typically harbors a worse prognosis compared to ER-positive EC. The molecular basis for the loss of NHR expression in endometrial tumors and its contribution to poor survival is largely unknown. Furthermore, there are no tools to systematically identify tumors that lose NHR mRNA expression relative to normal tissue. The development of such an approach could identify sets of NHR-based biomarkers for classifying patients into subgroups with poor survival outcomes. METHODS Here, a new computational method, termed receptLoss, was developed for identifying NHR expression loss in endometrial cancer relative to adjacent normal tissue. When applied to gene expression data from The Cancer Genome Atlas (TCGA), receptLoss identified 6 NHRs that were highly expressed in normal tissue and exhibited expression loss in a subset of endometrial tumors. RESULTS Three of the six identified NHRs - estrogen, progesterone, and androgen receptors - that are known to lose expression in ECs were correctly identified by receptLoss. Additionally, a novel association was found between thyroid hormone receptor beta (THRB) expression loss, increased expression of miRNA-146a, and increased rates of 5-year survival in the EC TCGA patient cohort. THRB expression loss occurs independently of estrogen and progesterone expression loss, suggesting the discovery of a distinct, clinically-relevant molecular subgroup. CONCLUSION ReceptLoss is a novel, open-source software tool to systematically identify NHR expression loss in cancer. The application of receptLoss to endometrial cancer gene expression data identified THRB, a previously undescribed biomarker of survival in endometrial cancer. Applying receptLoss to expression data from additional cancer types could lead to the development of biomarkers of disease progression for patients with any other tumor type. ReceptLoss can be applied to expression data from additional cancer types with the goal of identifying biomarkers of differential survival.
Collapse
Affiliation(s)
- Daniel G. Piqué
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
| | - John M. Greally
- Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
| | - Jessica C. Mar
- Department of Systems and Computational Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461 USA
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Building 75, Cnr. College Rd & Cooper Rd, Brisbane, QLD 4072 Australia
| |
Collapse
|
|
37
|
Murphy KP, Hendley MA, Patterson AT, Hall HE, Carter GJ, Isely C, Gower RM. Modulation of adipocyte size and fat pad weight via resveratrol releasing scaffolds implanted into the epididymal adipose tissue. J Biomed Mater Res A 2020; 109:766-778. [PMID: 32681806 DOI: 10.1002/jbm.a.37063] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 01/10/2023]
Abstract
Lipid overload of the adipose tissue, which can be caused by overnutrition, underlies metabolic disease. We hypothesized that increasing the energy demand of adipose tissue is a promising strategy to combat excessive lipid accumulation. Resveratrol, a natural polyphenol, activates lipid catabolism in fat tissue; however, its clinical success is hindered by poor bioavailability. Here, we implanted resveratrol releasing poly(lactide-co-glycolide) scaffolds into epididymal fat to overcome its poor bioavailability with the goal of enhancing local lipid catabolism. In lean mice, resveratrol scaffolds decreased adipocyte size relative to scaffolds with no drug, a response that correlated with AMP kinase activation. Immunohistochemistry indicated that macrophages and multinucleated giant cells within the scaffold expressed carnitine palmitoyltransferase 1 (CPT1) at higher levels than other cells in the adipose tissue. Furthermore, resveratrol increased CPT1 levels in cultured macrophages. Taken together, we propose that resveratrol scaffolds decrease adipocyte size because resveratrol increases lipid utilization in scaffold-infiltrating immune cells, possibly through elevating CPT1 levels or activity. In a follow-up study, mice that received resveratrol scaffolds 28-day prior to a high-fat diet exhibited decreased weight gain, adipose tissue expansion, and adipocyte hypertrophy compared to mice with control scaffolds. Notably, this scaffold-based strategy required a single resveratrol administration compared to the daily regiment generally needed for oral administration. These results indicate that localized delivery of metabolism modulating agents to the adipose tissue may overcome issues with bioavailability and that the role of biomaterials should be further investigated in this therapeutic strategy for metabolic disease.
Collapse
Affiliation(s)
- Kendall P Murphy
- Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina, USA
| | - Michael A Hendley
- Biomedical Engineering Program, University of South Carolina, Columbia, South Carolina, USA
| | - Alexandra T Patterson
- Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina, USA
| | - Hayley E Hall
- Biomedical Engineering Program, University of South Carolina, Columbia, South Carolina, USA
| | - Griffin J Carter
- Biomedical Engineering Program, University of South Carolina, Columbia, South Carolina, USA
| | - Christopher Isely
- Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina, USA
| | - R Michael Gower
- Department of Chemical Engineering, University of South Carolina, Columbia, South Carolina, USA.,Biomedical Engineering Program, University of South Carolina, Columbia, South Carolina, USA
| |
Collapse
|
|
38
|
Banerjee A, Singh J. Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies. Bioeng Transl Med 2020; 5:e10150. [PMID: 32440558 PMCID: PMC7237149 DOI: 10.1002/btm2.10150] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 11/07/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Obesity-associated type 2 diabetes mellitus (T2DM) is characterized by low-grade chronic systemic inflammation that arises primarily from the white adipose tissue. The interplay between various adipose tissue-derived chemokines drives insulin resistance in T2DM and has therefore become a subject of rigorous investigation. The adipocytokines strongly associated with glucose homeostasis include tumor necrosis factor-α, various interleukins, monocyte chemoattractant protein-1, adiponectin, and leptin, among others. Remodeling the adipose tissue inflammasome in obesity-associated T2DM is likely to treat the underlying cause of the disease and bring significant therapeutic benefit. Various strategies have been adopted or are being investigated to modulate the serum/tissue levels of pro- and anti-inflammatory adipocytokines to improve glucose homeostasis in T2DM. These include use of small molecule agonists/inhibitors, mimetics, antibodies, gene therapy, and other novel formulations. Here, we discuss adipocytokines that are strongly associated with insulin activity and therapies that are under investigation for modulation of their levels in the treatment of T2DM.
Collapse
Affiliation(s)
- Amrita Banerjee
- Department of Pharmaceutical SciencesNorth Dakota State UniversityFargoNorth Dakota
| | - Jagdish Singh
- Department of Pharmaceutical SciencesNorth Dakota State UniversityFargoNorth Dakota
| |
Collapse
|
|
39
|
Abstract
COPD and Type 2 diabetes are two highly prevalent global health conditions associated
with high mortality and morbidity. The connection between these two common diseases is complex,
and more research is required for further understanding of these conditions. COPD is being
increasingly recognized as a risk factor for the development of type2 diabetes through different
mechanisms including systemic inflammation, obesity, hypoxia and use of corticosteroids. Also,
hyperglycemia in diabetes patients is linked to the adverse impact on lung physiology, and a possible
increase in the risk of COPD. In this review article, we discuss the studies demonstrating the
associations between COPD and Type 2 Diabetes, underlying pathophysiology and recommended
therapeutic approach in the management of patients with coexisting COPD and diabetes.
Collapse
Affiliation(s)
- Chaitanya Mamillapalli
- Springfield Clinic, Endocrinology, 1025 South 6th Street, Springfield, IL, 62702, United States
| | - Ramesh Tentu
- St. Davids Health care, Team health Hospitalist Service, Georgetown, TX 78626, United States
| | - Nitesh Kumar Jain
- Mercy Medical Centre, Pulmonology and Critical Care, Sioux City, IA 51104, United States
| | - Ramanath Bhandari
- Springfield Clinic, Endocrinology, 1025 South 6th Street, Springfield, IL, 62702, United States
| |
Collapse
|
|
40
|
2,4-Thiazolidinedione in Well-Fed Lactating Dairy Goats: I. Effect on Adiposity and Milk Fat Synthesis. Vet Sci 2019; 6:vetsci6020045. [PMID: 31108904 PMCID: PMC6632146 DOI: 10.3390/vetsci6020045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 04/29/2019] [Accepted: 05/14/2019] [Indexed: 12/20/2022] Open
Abstract
Background: In a prior experiment, treatment of goats with the putative PPARγ agonist 2,4-thiazolidinedione (2,4-TZD) did not affect milk fat or expression of milk-fat related genes. The lack of response was possibly due to deficiency of vitamin A and/or a poor body condition of the animals. In the present experiment, we tested the hypothesis that PPARγ activation affects milk fat synthesis in goats with a good body condition and receiving adequate levels of vitamin A. Methods: Lactating goats receiving a diet that met NRC requirements, including vitamin A, were injected with 8 mg/kg BW of 2,4-TZD (n = 6) or saline (n = 6; CTR) daily for 26 days. Blood metabolic profiling and milk yield and components were measured including fatty acid profile. Expression of genes related to glucose and lipid metabolism was measured in adipose tissue and in mammary epithelial cells (MEC). Size of adipocytes was assessed by histological analysis. Results: NEFA, BHBA, and fatty acids available in plasma decreased while glucose increased in 2,4-TZD vs. CTR. Size of cells and expression of insulin signaling and glucose metabolism-related genes were larger in 2,4-TZD vs. CTR in adipose tissue. In MEC, expression of SCD1 and desaturation of stearate was lower in 2,4-TZD vs. CTR. Conclusions: Overall data revealed a lack of PPARγ activation by 2,4-TZD and no effect on milk fat synthesis despite a strong anti-lipolysis effect on adipose tissue.
Collapse
|
|
41
|
Patel K, Zafar M, Ziganshin B, Elefteriades J. Diabetes Mellitus: Is It Protective against Aneurysm? A Narrative Review. Cardiology 2018; 141:107-122. [DOI: 10.1159/000490373] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 05/24/2018] [Indexed: 11/19/2022]
Abstract
Objectives: In the course of extensive clinical aortic surgery, we noticed that the aorta was quite thick and fibrotic in diabetic patients. We thought the diabetic aortic aorta might be inimitable to aortic dissection. On this basis, we set out to review information in the literature regarding aortic growth and dissection in diabetic patients. Methods: We used a 2-step search approach to the available literature on diabetes and aneurysm. Firstly, databases including PubMed, Cochrane, Embase and TRIP were searched. Secondly, relevant studies were identified through secondary sources including references of initially selected articles. We address the relationship between diabetes and the incidence, prevalence, growth, mortality and rupture of an aneurysm. Results: Diabetes is thought to exert a protective role in both thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). Diabetics were shown to have a slower aneurysm growth rate, lower rupture rate, delayed (> 65 years) age of rupture, decreased rate of mortality from an aneurysm and a decreased length of hospital stay. There was also noted a decreased rate of incidence and prevalence of TAA and AAA in diabetics, smaller aneurysm diameter, reduction in matrix metalloproteinases and an increased aortic wall stress in diabetics. Antidiabetic agents like metformin, thiazolidinediones and dipeptidyl peptidase-4 inhibitors may protect against an aneurysm. Conclusion: Our literature review provides strong (but often circumstantial) evidence that diabetic patients exhibit slower growth of aortic aneurysms and a lower rate of aortic dissection. Furthermore, clinical and experimental studies indicate that common antidiabetic medications on their own inhibit growth of aortic aneurysms. These findings indicate a paradoxically beneficial effect of the otherwise highly detrimental diabetic state.
Collapse
|
|
42
|
Illés P, Grycová A, Krasulová K, Dvořák Z. Effects of Flavored Nonalcoholic Beverages on Transcriptional Activities of Nuclear and Steroid Hormone Receptors: Proof of Concept for Novel Reporter Cell Line PAZ-PPARg. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018; 66:12066-12078. [PMID: 30394742 DOI: 10.1021/acs.jafc.8b05158] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
We developed and characterized a novel human luciferase reporter cell line for the assessment of peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity, PAZ-PPARg. The luciferase activity induced by PPARγ endogenous agonist 15d-PGJ2 and prostaglandin PGD2 reached mean values of (87.9 ± 14.0)-fold and (89.6 ± 19.7)-fold after 24 h of exposure to 40 μM 15d-PGJ2 and 70 μM PGD2, respectively. A concentration-dependent inhibition of 15d-PGJ2- and PGD2-induced luciferase activity was observed after the application of T0070907, a selective antagonist of PPARγ, which confirms the specificity of response to both agonists. The PAZ-PPARg cell line, along with the reporter cell lines for the assessment of transcriptional activities of thyroid receptor (TR), vitamin D3 receptor (VDR), androgen receptor (AR), and glucocorticoid receptor (GR), were used for the screening of 27 commonly marketed flavored nonalcoholic beverages for their possible disrupting effects. Our findings indicate that some of the examined beverages have the potential to modulate the transcriptional activities of PPARγ, VDR, and AR.
Collapse
Affiliation(s)
- Peter Illés
- Regional Centre of Advanced Technologies and Materials, Faculty of Science , Palacky University , Slechtitelu 27 , 783 71 Olomouc , Czech Republic
| | - Aneta Grycová
- Regional Centre of Advanced Technologies and Materials, Faculty of Science , Palacky University , Slechtitelu 27 , 783 71 Olomouc , Czech Republic
| | - Kristýna Krasulová
- Regional Centre of Advanced Technologies and Materials, Faculty of Science , Palacky University , Slechtitelu 27 , 783 71 Olomouc , Czech Republic
| | - Zdeněk Dvořák
- Regional Centre of Advanced Technologies and Materials, Faculty of Science , Palacky University , Slechtitelu 27 , 783 71 Olomouc , Czech Republic
| |
Collapse
|
|
43
|
The IRE1α-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARγ activity. Exp Mol Med 2018; 50:1-15. [PMID: 30111834 PMCID: PMC6093883 DOI: 10.1038/s12276-018-0131-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 04/09/2018] [Accepted: 04/20/2018] [Indexed: 01/06/2023] Open
Abstract
The peroxisome proliferator-activated receptor-γ (PPARγ) improves whole-body insulin sensitivity by regulating the adipogenic and metabolic functions of mature adipocytes. We have previously demonstrated that an active splice variant of X-box binding protein 1 (XBP1s) enhances PPARγ expression during adipogenesis. In this study, we investigated the role of XBP1s, particularly with respect to PPARγ, in the mechanisms underlying insulin sensitivity in mature adipocytes. Insulin was able to stimulate XBP1s generation by activating inositol-requiring enzyme 1 (IRE1) α and was also able to increase its transcriptional activity by inducing nuclear translocation. XBP1s also upregulated the levels of phosphorylated IRS1 and AKT, demonstrating a positive feedback regulatory mechanism linking insulin and XBP1s. XBP1s enhanced the expression of fibroblast growth factor 21 and, in turn, increased PPARγ activity, translocation of GLUT4 to the cell surface, and glucose uptake rate in adipocytes. In addition, XBP1s abolished palmitate-induced insulin resistance in adipocytes by increasing adiponectin secretion, repressing the secretion of pro-inflammatory adipokines such as leptin, monocyte chemoattractant protein 1, and tumor necrosis factor α, and decreasing fatty acid release. These findings provide a novel mechanism by which XBP1s stimulate insulin sensitivity in adipocytes through fibroblast growth factor 21 induction and PPARγ activation.
Collapse
|
|
44
|
Khosravi F, Kharazmi F, Kamran M, Malekzadeh K, Talebi A, Soltani N. The role of PPAR-γ and NFKB genes expression in muscle to improve hyperglycemia in STZ-induced diabetic rat following magnesium sulfate administration. INTERNATIONAL JOURNAL OF PHYSIOLOGY, PATHOPHYSIOLOGY AND PHARMACOLOGY 2018; 10:124-131. [PMID: 30042813 PMCID: PMC6055085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 06/19/2018] [Indexed: 06/08/2023]
Abstract
The present study was designed to investigate the possible role of magnesium (Mg2+) on activation of the peroxisome proliferator-activated receptor gamma (PPAR-γ) and inhibition of nuclear factor-KB (NFKB p65) in muscle to increase glucose transporter 4 (GLUT4) gene expression. Fifty rats were divided into five groups, namely non-diabetic control (NDC), Mg2+-treated non-diabetic control (Mg2+-NDC), chronic diabetic (CD), Mg2+-treated chronic diabetic (Mg2+-CD), and insulin-treated chronic diabetic (Ins-CD). Diabetes was induced with streptozotocin (STZ) injection. The Mg2+-CD and Mg2+-NDC groups received 10 g/l of magnesium sulfate (MgSO4) added to drinking water and Ins-CD group received 2.5 U/kg of insulin. The blood glucose level and body weight were measured every week. After 16 weeks, intraperitoneal glucose tolerance test (IPGTT) was done and then animals were decapitated, blood samples were taken to determine the plasma levels of Mg2+ and gastrocnemius muscle legs were isolated for both PPAR-γ and NFKB (p65) genes and proteins expression. Administration of MgSO4 improved IPGTT, lowered blood glucose levels and increased PPAR-γ gene and protein expression. Diabetes increased NFKB gene and protein expression. Although Mg2+ therapy could not decrease NFKB (p65) gene expression, the protein decreased by Mg2+ therapy. Insulin decreased NFKB (p65) gene and protein expression, without any effect on PPAR-γ gene and protein expression. According to our findings it seems that suppressing NFKB (p65) protein synthesis and increases in PPAR-γ gene and protein expression could help Mg2+ administration to decreases blood glucose levels. But decreasing in NFKB (p65) gene and protein expression help insulin to decrease blood glucose level.
Collapse
Affiliation(s)
- Fatemeh Khosravi
- Molecular Medicine Research Center and Hormozgan Health Institute, Hormozgan University of Medical ScienceBandar Abbas, Iran
- Physiology Department, Faculty of Medicine, Hormozgan University of Medical ScienceBandar Abbas, Iran
| | - Fatemeh Kharazmi
- Molecular Medicine Research Center and Hormozgan Health Institute, Hormozgan University of Medical ScienceBandar Abbas, Iran
- Physiology Department, Faculty of Medicine, Hormozgan University of Medical ScienceBandar Abbas, Iran
| | - Mitra Kamran
- Molecular Medicine Research Center and Hormozgan Health Institute, Hormozgan University of Medical ScienceBandar Abbas, Iran
- Physiology Department, Faculty of Medicine, Hormozgan University of Medical ScienceBandar Abbas, Iran
| | - Kianoosh Malekzadeh
- Molecular Medicine Research Center and Hormozgan Health Institute, Hormozgan University of Medical ScienceBandar Abbas, Iran
| | - Ardeshir Talebi
- Department of Clinical Pathology, Faculty of Medicine, Isfahan University of Medical ScienceIsfahan, Iran
| | - Nepton Soltani
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical ScienceBandar Abbas, Iran
- Department of Physiology, Faculty of Medicine, Isfahan University of Medical ScienceIsfahan, Iran
| |
Collapse
|
|
45
|
Park JS, Lee H, Choi BW, Ro S, Lee D, Na JE, Hong JH, Lee JS, Kim BW, Ko YG. An MG53-IRS1-interaction disruptor ameliorates insulin resistance. Exp Mol Med 2018; 50:1-12. [PMID: 29884820 PMCID: PMC5994830 DOI: 10.1038/s12276-018-0099-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Revised: 03/08/2018] [Accepted: 03/16/2018] [Indexed: 12/24/2022] Open
Abstract
Mitsugumin 53 (MG53) is an E3 ligase that induces insulin receptor substrate-1 (IRS-1) ubiquitination and degradation in skeletal muscle. We previously demonstrated that the pharmaceutical disruption of the MG53-IRS-1 interaction improves insulin sensitivity by abrogating IRS-1 ubiquitination and increasing IRS-1 levels in C2C12 myotubes. Here, we developed a novel MG53-IRS-1 interaction disruptor (MID-00935) that ameliorates insulin resistance in diet-induced obese (DIO) mice. MID-00935 disrupted the molecular interaction of MG53 and IRS-1, abrogated MG53-induced IRS-1 ubiquitination and degradation and improved insulin signaling in C2C12 myotubes. Oral administration of MID-00935 increased insulin-induced IRS-1, Akt, and Erk phosphorylation via increasing IRS-1 levels in the skeletal muscle of DIO mice. In DIO mice, MID-00935 treatment lowered fasting blood glucose levels and improved glucose disposal in glucose and insulin tolerance tests. These results suggest that MID-00935 may be a potential muscle-targeting drug candidate for treating insulin resistance.
Collapse
Affiliation(s)
- Jun Sub Park
- Division of Life Sciences, Korea University, Seoul, Korea.,Tunneling Nanotube Research Center, Korea University, Seoul, Korea
| | - Hyun Lee
- Division of Life Sciences, Korea University, Seoul, Korea.,Tunneling Nanotube Research Center, Korea University, Seoul, Korea
| | - Bo Woon Choi
- Division of Life Sciences, Korea University, Seoul, Korea.,Tunneling Nanotube Research Center, Korea University, Seoul, Korea
| | - Seonggu Ro
- CrystalGenomics, Inc., Seongnam-si, Gyeonggi-do, Korea
| | - Doyoung Lee
- CrystalGenomics, Inc., Seongnam-si, Gyeonggi-do, Korea
| | - Jeong Eun Na
- CrystalGenomics, Inc., Seongnam-si, Gyeonggi-do, Korea
| | - Jeoung-Ho Hong
- Division of Life Sciences, Korea University, Seoul, Korea.,Tunneling Nanotube Research Center, Korea University, Seoul, Korea
| | - Jae-Seon Lee
- Department of Molecular Medicine, College of Medicine, INHA University, Incheon, Korea
| | - Bong-Woo Kim
- Division of Life Sciences, Korea University, Seoul, Korea. .,Tunneling Nanotube Research Center, Korea University, Seoul, Korea.
| | - Young-Gyu Ko
- Division of Life Sciences, Korea University, Seoul, Korea. .,Tunneling Nanotube Research Center, Korea University, Seoul, Korea.
| |
Collapse
|
|
46
|
Tanaka A, Komukai S, Shibata Y, Yokoi H, Iwasaki Y, Kawasaki T, Horiuchi K, Nakao K, Ueno T, Nakashima H, Tamashiro M, Hikichi Y, Shimomura M, Tago M, Toyoda S, Inoue T, Kawaguchi A, Node K. Effect of pioglitazone on cardiometabolic profiles and safety in patients with type 2 diabetes undergoing percutaneous coronary artery intervention: a prospective, multicenter, randomized trial. Heart Vessels 2018; 33:965-977. [PMID: 29487991 DOI: 10.1007/s00380-018-1143-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 02/23/2018] [Indexed: 12/18/2022]
Abstract
Pioglitazone has superior antiatherosclerotic effects compared with other classes of antidiabetic agents, and there is substantial evidence that pioglitazone improves cardiovascular (CV) outcomes. However, there is also a potential risk of worsening heart failure (HF). Therefore, it is clinically important to determine whether pioglitazone is safe in patients with type 2 diabetes mellitus (T2DM) who require treatment for secondary prevention of CV disease, since they have an intrinsically higher risk of HF. This prospective, multicenter, open-label, randomized study investigated the effects of pioglitazone on cardiometabolic profiles and CV safety in T2DM patients undergoing elective percutaneous coronary intervention (PCI) using bare-metal stents or first-generation drug-eluting stents. A total of 94 eligible patients were randomly assigned to either a pioglitazone or conventional (control) group, and pioglitazone was started the day before PCI. Cardiometabolic profiles were evaluated before PCI and at primary follow-up coronary angiography (5-8 months). Pioglitazone treatment reduced HbA1c levels to a similar degree as conventional treatment (pioglitazone group 6.5 to 6.0%, P < 0.01; control group 6.5 to 5.9%, P < 0.001), without body weight gain. Levels of high-molecular weight adiponectin increased more in the pioglitazone group than the control group (P < 0.001), and the changes were irrespective of baseline glycemic control. Furthermore, pioglitazone significantly reduced plasma levels of natriuretic peptides and preserved cardiac systolic and diastolic function (assessed by echocardiography) without incident hospitalization for worsening HF. The incidence of clinical adverse events was also comparable between the groups. These results indicate that pioglitazone treatment before and after elective PCI may be tolerable and clinically safe and may improve cardiometabolic profiles in T2DM patients.
Collapse
Affiliation(s)
- Atsushi Tanaka
- Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, Japan.
| | - Sho Komukai
- Clinical Research Center, Saga University Hospital, Saga, Japan
| | - Yoshisato Shibata
- Miyazaki Medical Association Hospital, Cardiovascular Center, Miyazaki, Japan
| | - Hiroyoshi Yokoi
- Department of Cardiology, Kokura Memorial Hospital, Kitakyushu, Japan
| | - Yoshihiro Iwasaki
- Department of Cardiology, Nagasaki Kouseikai Hospital, Nagasaki, Japan
| | - Tomohiro Kawasaki
- Department of Cardiology, Cardiovascular Center, Shin-Koga Hospital, Kurume, Japan
| | - Kenji Horiuchi
- Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto, Japan
| | - Koichi Nakao
- Division of Cardiology, Saiseikai Kumamoto Hospital Cardiovascular Center, Kumamoto, Japan
| | - Takafumi Ueno
- Division of Cardiovascular Medicine, Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Hitoshi Nakashima
- Department of Cardiology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan
| | | | - Yutaka Hikichi
- Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, Japan
| | - Mitsuhiro Shimomura
- Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, Japan
| | - Motoko Tago
- Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, Japan
| | - Shigeru Toyoda
- Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan
| | - Teruo Inoue
- Department of Cardiovascular Medicine, Dokkyo Medical University, Mibu, Japan
| | | | - Koichi Node
- Department of Cardiovascular Medicine, Saga University, 5-5-1 Nabeshima, Saga, Japan.
| | | |
Collapse
|
|
47
|
Satish S, Srivastava A, Yadav P, Varshney S, Choudhary R, Balaramnavar VM, Narender T, Gaikwad AN. Aegeline inspired synthesis of novel amino alcohol and thiazolidinedione hybrids with antiadipogenic activity in 3T3-L1 cells. Eur J Med Chem 2018; 143:780-791. [DOI: 10.1016/j.ejmech.2017.11.041] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Revised: 11/15/2017] [Accepted: 11/17/2017] [Indexed: 12/14/2022]
|
|
48
|
de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention of cardiovascular disease. A meta-analysis of randomized-controlled trials. Cardiovasc Diabetol 2017; 16:134. [PMID: 29037211 PMCID: PMC5644073 DOI: 10.1186/s12933-017-0617-4] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 10/06/2017] [Indexed: 12/20/2022] Open
Abstract
Background and aims Pioglitazone targets multiple pathogenic pathways involved in the development of cardiovascular diseases (CVD). The aim of this systematic review and meta-analysis is to assess the effects of pioglitazone treatment on the secondary prevention of CVD. Methods Randomized-controlled trials of pioglitazone in patients with CVD were identified through PubMed, Embase, Cochrane and CINAHL, in a search up to May 2016. Studies were included if pioglitazone was compared with any control (usual care, placebo or active comparator) and if patients were previously diagnosed with CVD. The outcomes of interest included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, all-cause mortality and heart failure (HF). All outcomes were compared by pooled risk ratios (RR) with a 95% confidence interval (CI). Pooled estimates were calculated using a random-effects model. Results Ten studies reported the effects of pioglitazone on any of the outcomes of interest. Pioglitazone reduced recurrent MACE (RR 0.74, 95% 0.60–0.92; I2 = 35), MI (RR 0.77, 95% CI 0.64–0.93; I2 = 0%), or stroke (RR 0.81, 95% CI 0.68–0.96; I2 = 0%). Pioglitazone did not reduce all-cause mortality (RR 0.94, 95% CI 0.81–1.08; I2 = 0%), whereas pioglitazone treatment was associated with an increased risk of HF (RR 1.33, 95% CI 1.14–1.54). Conclusions Pioglitazone lowers the risk of recurrent MACE, stroke, or MI in patients with clinical manifest vascular disease. Pioglitazone does not lower the risk for all-cause mortality, and increases the risk for the development of HF. Electronic supplementary material The online version of this article (doi:10.1186/s12933-017-0617-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Marit de Jong
- Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508, Utrecht, GA, The Netherlands
| | - H Bart van der Worp
- Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yolanda van der Graaf
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Frank L J Visseren
- Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jan Westerink
- Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508, Utrecht, GA, The Netherlands.
| |
Collapse
|
|
49
|
Kumar Singh A, Tripathi AC, Tewari A, Chawla V, Saraf SK. Design and microwave facilitated green synthesis of 2-[4-(3-carboxymethyl, methoxy carbonylmethyl-2,4-dioxo and 4-oxo-2-thioxo-thiazolidin-5-ylidenemethyl)-phenoxy]-2 and 3-methyl propionic acid ethyl ester derivatives: a novel structural class of antidyslipidemic agents. Med Chem Res 2017. [DOI: 10.1007/s00044-017-1875-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
|
|
50
|
Yadollah S, Kazemipour N, Bakhtiyari S, Nazifi S. Palmitate-induced insulin resistance is attenuated by Pioglitazone and EGCG through reducing the gluconeogenic key enzymes expression in HepG2 cells. J Med Life 2017; 10:244-249. [PMID: 29362600 PMCID: PMC5771254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
HYPOTHESIS Palmitate causes insulin resistance (IR) in insulin target tissue. Pioglitazone (an anti-hyperglycemic agent) and epigallocatechin gallate (EGCG, a dietary supplement) can be used for the treatment of type 2 diabetes. However, their molecular effects on gluconeogenesis remain unclear. OBJECTIVE Hence, we aimed to investigate the simultaneous effect of these anti-hyperglycemic agents on gluconeogenesis through in vitro experiments. METHODS HepG2 cells were treated with 0.5 mM palmitate, 10 μM pioglitazone, and 40 μM epigallocatechin gallate (EGCG). Gene expression assay was used to investigate the underlying mechanism. Glucose production assay was applied in culture medium to evaluate the activity of gluconeogenesis pathway. RESULTS Palmitate induced IR could significantly increase G6Pase and PEPCK gene expressions by 58 and 30%, respectively, compared to the control. EGCG reduced the expression of PEPCK and G6Pase by 53 and 67%, respectively. Pioglitazone reduced the mRNA level of PEPCK and G6Pase by 58 and 62% respectively. Combined treatment of insulin-resistant cells with EGCG and pioglitazone significantly decreased the mRNA level of PEPCK and G6Pase by 73 and 80%, respectively. Treatment with palmitate increased glucose production by 50% in HepG2 cells. When the insulin resistant HepG2 cells were treated alone with EGCG and pioglitazone, the glucose production reduced by 50 and 55%, respectively. The combined treatment with EGCG and pioglitazone resulted in 69% reduction in glucose production compared to the palmitate treated HepG2 cells. CONCLUSIONS These data suggest the additive inhibitory effect of co-treatment with pioglitazone and EGCG on the gluconeogenesis pathway in palmitate-induced insulin resistance HepG2 cells.
Collapse
Affiliation(s)
- S Yadollah
- Department of Basic Science, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - N Kazemipour
- Department of Basic Science, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| | - S Bakhtiyari
- Department of Clinical Biochemistry, Faculty of Medicine, Ilam University of Medical Sciences, Ilam, Iran
| | - S Nazifi
- Department of Clinical Pathology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran
| |
Collapse
|