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Kumar M, Muthurayar T, Karthika S, Gayathri S, Varalakshmi P, Ashokkumar B. Anti-Diabetic Potentials of Lactobacillus Strains by Modulating Gut Microbiota Structure and β-Cells Regeneration in the Pancreatic Islets of Alloxan-Induced Diabetic Rats. Probiotics Antimicrob Proteins 2025; 17:1096-1116. [PMID: 38329697 DOI: 10.1007/s12602-024-10221-7] [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] [Accepted: 01/17/2024] [Indexed: 02/09/2024]
Abstract
Diabetes mellitus, a most common endocrine disorder of glucose metabolism, has become a global epidemic and poses a serious public health threat with an increased socio-economic burden. Escalating incidence of diabetes is correlated with changes in lifestyle and food habits that cause gut microbiome dysbiosis and β-cells damage, which can be addressed with dietary interventions containing probiotics. Hence, the search for probiotics of human origin with anti-diabetic, anti-AGE, and anti-ACE potentials has gained renewed interest for the effective management of diabetes and its associated complications. The present study used an alloxan (AXN)-induced diabetic rat model to investigate the effects of potential probiotic Lacticaseibacillus casei MKU1, Lactiplantibacillus pentosus MKU3, and Lactiplantibacillus plantarum MKU7 administration individually on physiochemical parameters related to diabetic pathogenesis. Experimental animals were randomly allotted into six groups viz. NCG (control), DCG (AXN), DGM (metformin), DGP1 (MKU1), DGP2 (MKU3), and DGP3 (MKU7), and biochemical data like serum glucose, insulin, AngII, ACE, HbA1c, and TNF-α levels were measured until 90 days. Our results suggest that oral administration with MKU1, MKU3, or MKU7 significantly improved serum insulin levels, glycemic control, glucose tolerance, and body weight. Additionally, β-cell mass was increased by preserving islet integrity in Lactobacillus-treated diabetic rats, whereas TNF-α (~40%), AngII (~30%), and ACE levels (~50%) were strongly inhibited and enhanced sIgA production (5.8 folds) abundantly. Furthermore, Lactobacillus administration positively influenced the gut microbiome with a significant increase in the abundance of Lactobacillus species and the beneficial Bacteroides uniformis and Bacteroides fragilis, while decreased the pathogenic Proteus vulgaris and Parabacteroides distasonis. Among the probiotic treatment groups, L. pentosus MKU3 performed greatly in almost all parameters, indicating its potential use for alleviating diabetes-associated complications.
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Affiliation(s)
- Manoj Kumar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Tharmar Muthurayar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Sukumaran Karthika
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Santhalingam Gayathri
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Perumal Varalakshmi
- Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai, India
| | - Balasubramaniem Ashokkumar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India.
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Alsaedi AQ, Nader MA, El-Kashef DH, Abdelmageed ME. Mangiferin mitigates dexamethasone-induced insulin resistance in rats: insight into vascular dysfunction and hepatic steatosis. Front Pharmacol 2025; 16:1572758. [PMID: 40406487 PMCID: PMC12095298 DOI: 10.3389/fphar.2025.1572758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 04/08/2025] [Indexed: 05/26/2025] Open
Abstract
Aim Insulin resistance (IR) is a hazard to human health in which peripheral insulin-target organs, like the liver, become less sensitive to normal levels of insulin. Dexamethasone (DEX)-induced IR is a distinct model of IR. Hence, the present study investigates the efficacy of mangiferin (Mang) in the reversal of DEX-induced IR in the livers and aortas of rats. Main methods Rats were randomly assigned into six groups: control (CTRL), Mang, DEX, and three pretreated groups (received Mang 25 mg/kg, 50 mg/kg, or 100 mg/kg, orally for 14 days, with DEX (1 mg/kg) injected from day 8 to day 14). On day 15, serum, liver, and aorta tissues were obtained and examined using biochemical, histological, and immunohistochemical assessments. Key findings Mang administration attenuated DEX-induced IR, evidenced by decreased oral glucose tolerance test (OGTT) and fasting serum insulin levels, in addition to improving the DEX-induced hepatic and aortic histopathological alterations. Additionally, Mang attenuated DEX-induced alterations in liver function parameters and improved serum lipid profiles, oxidative stress, and antioxidant biomarkers. Mang also markedly increased hepatic and aortic levels of insulin receptor substrate 1 (IRS1), protein kinase B (AKT), AMP-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-gamma (PPAR-γ) levels. Mang reduced hepatic and aortic tumor necrosis factor-alpha (TNF-α), forkhead box protein O1 (FOXO-1), hepatic NOD-like receptor family pyrin domain-containing 3 (NLRP3), phosphoenol pyruvate carboxy kinase (PEPCK), and glucose 6-phosphatase (G6Pase). Mang elevated hepatic glycogen synthase kinase3 (GSK3α) and glycogen synthase (GS2) levels. Furthermore, Mang ameliorated aortic expression levels of endothelin-1 (ET-1), vascular cell adhesion molecule-1 (VCAM), c-Jun N-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and vascular endothelial growth factor (VEGF) and increased endothelial nitric oxide synthase (eNOS) and prostacyclin (PGI2) levels. Conclusion Mang administration could confer hepato- and vasculo-protective activity via its hypolipidemic, hepatoprotective, anti-inflammatory, and antioxidant efficacy.
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Affiliation(s)
- Abdullah Q. Alsaedi
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Quality and Output Control, Branch of Ministry of Health, Madinah, Saudi Arabia
| | - Manar A. Nader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt
| | - Dalia H. El-Kashef
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Marwa E. Abdelmageed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura National University, Gamasa, Egypt
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3
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Zhao X, Huang F, Sun Y, Li L. Mechanisms of endurance and resistance exercise in type 2 diabetes mellitus: A Narrative review. Biochem Biophys Res Commun 2025; 761:151731. [PMID: 40179737 DOI: 10.1016/j.bbrc.2025.151731] [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: 01/20/2025] [Revised: 03/18/2025] [Accepted: 03/28/2025] [Indexed: 04/05/2025]
Abstract
In the treatment and management of type 2 diabetes mellitus (T2DM), exercise therapy has received increasing attention due to its accessibility and cost-effectiveness. Regular physical exercise improves glycemic control by ameliorating insulin resistance (IR) and reducing the risk of complications. However, the distinct mechanisms underlying the efficacy of endurance training (ET) and resistance training (RT) in T2DM remain incompletely understood. This review systematically compares the molecular pathways through which ET and RT improve IR, focusing on epigenetic regulation, metabolic reprogramming, and anti-inflammatory effects. We highlight that RT enhances protein synthesis via the IGF-1/PI3K/AKT/mTOR pathway, while ET predominantly improves mitochondrial biogenesis and lipid oxidation through AMPK/SIRT1/PGC-1α signaling. Additionally, ET exerts immunomodulatory effects by suppressing pro-inflammatory cytokines (e.g., TNF-α) and elevating anti-inflammatory myokines (e.g., IL-6). These findings provide a mechanistic basis for personalized exercise prescriptions in T2DM management.
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Affiliation(s)
- Xinwen Zhao
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China; Norman Bethune College of Medicine, Jilin University, Changchun, 130021, China
| | - Fengwei Huang
- Norman Bethune College of Medicine, Jilin University, Changchun, 130021, China
| | - Yidi Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, Jilin Province, China.
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Singh P, Singh DP, Patel MK, Binwal M, Kaushik A, Mall M, Sahu M, Khare P, Shanker K, Bawankule DU, Sundaresan V, Mani DN, Shukla AK. Vindoline is a key component of Catharanthus roseus leaf juice extract prepared through an Ayurveda-based method for ameliorating insulin-resistant type 2 diabetes. PROTOPLASMA 2025; 262:667-681. [PMID: 39794517 DOI: 10.1007/s00709-024-02026-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 12/22/2024] [Indexed: 01/13/2025]
Abstract
Catharanthus roseus leaves have been traditionally described to possess potent antidiabetic activity and some leaf-specific alkaloids, including vindoline, have been studied for their antidiabetic potential. The aim of the present study was to validate the antidiabetic property of the plant with special reference to vindoline. An Ayurveda-based method was used to prepare the Swaras [leaf juice extract (LJE)] of three familial C. roseus genotypes differing in their vindoline content [CIM-Sushil (CS) > Dhawal (D) > Nirmal (N)]. In vivo experiments using LJE were performed in Charles Foster rats, whereby metformin (M100, 100 mg/kg BW) and vindoline (V20, 20 mg/kg BW) were used for comparison. OGTT-based screening for LJE doses (N100, N300, N500, D100, D200, D300, CS100, CS200, CS300 mg/kg BW) was carried out. Further analysis of the effective doses (D100, D200, D300, CS100, CS200, CS300) in streptozotocin-induced diabetic rats indicated highest blood glucose depletion in D300 (52.51%) and CS200 (64.55%) together with V20 (56.96%) on the 14th day. CS-LJE was found to be safe up to 2000 mg/kg BW. The role of LJE/vindoline in maintaining glucose homeostasis in liver was found to be mediated through the expression of insulin pathway genes (IRS-1, PI3K, AKT, GLUT2). TNF-α-induced insulin resistance in L6 skeletal muscle cells was used to analyze the effect of LJE/vindoline through glucose uptake assay and expression analysis of insulin pathway genes (IRS-1, PI3K, AKT, GLUT4). The results indicated that the antidiabetic effect of LJE/vindoline is mediated through activation of IRS/PI3K/AKT/GLUT signaling pathway.
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Affiliation(s)
- Pooja Singh
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
| | - Dewasya P Singh
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Manish K Patel
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
| | - Monika Binwal
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Amit Kaushik
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Maneesha Mall
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
| | - Mridula Sahu
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
| | - Puja Khare
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Karuna Shanker
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Dnyaneshwar U Bawankule
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Velusamy Sundaresan
- CSIR-Central Institute of Medicinal and Aromatic Plants, Research Centre, Allalasandra, GKVK Post, Bengaluru, 560065, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India
| | - Daya N Mani
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
| | - Ashutosh K Shukla
- CSIR-Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow, 226015, Uttar Pradesh, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, Uttar Pradesh, India.
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Panwar A, Malik SO, Adib M, Lopaschuk GD. Cardiac energy metabolism in diabetes: emerging therapeutic targets and clinical implications. Am J Physiol Heart Circ Physiol 2025; 328:H1089-H1112. [PMID: 40192025 DOI: 10.1152/ajpheart.00615.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 10/15/2024] [Accepted: 04/01/2025] [Indexed: 04/25/2025]
Abstract
Patients with diabetes are at an increased risk for developing diabetic cardiomyopathy and other cardiovascular complications. Alterations in cardiac energy metabolism in patients with diabetes, including an increase in mitochondrial fatty acid oxidation and a decrease in glucose oxidation, are important contributing factors to this increase in cardiovascular disease. A switch from glucose oxidation to fatty acid oxidation not only decreases cardiac efficiency due to increased oxygen consumption but it can also increase reactive oxygen species production, increase lipotoxicity, and redirect glucose into other metabolic pathways that, combined, can lead to heart dysfunction. Currently, there is a lack of therapeutics available to treat diabetes-induced heart failure that specifically target cardiac energy metabolism. However, it is becoming apparent that part of the benefit of existing agents such as GLP-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors may be related to their effects on cardiac energy metabolism. In addition, direct approaches aimed at inhibiting cardiac fatty acid oxidation or increasing glucose oxidation hold future promise as potential therapeutic approaches to treat diabetes-induced cardiovascular disease.
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Affiliation(s)
- Archee Panwar
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Sufyan O Malik
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Muhtasim Adib
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Gary D Lopaschuk
- Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
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Lin S, Jensen MD. Human Adipose Tissue Metabolism in Obesity. J Obes Metab Syndr 2025; 34:105-119. [PMID: 40194889 PMCID: PMC12066998 DOI: 10.7570/jomes25025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Revised: 03/21/2025] [Accepted: 03/21/2025] [Indexed: 04/09/2025] Open
Abstract
The scientific understanding of adipose tissue has advanced tremendously during the past decade. Once thought to be an inert fat storage organ, we now know that adipose tissue serves important functions in energy balance and endocrinology, as well as playing a central role in the development of metabolic diseases. Adipose tissue lipid storage and lipolysis are tightly controlled by hormones, such as insulin, in response to the body's energy needs. Adipose insulin sensitivity can be measured in vivo in humans using isotopic fatty acid tracers and the insulin clamp technique. These data allow investigators to calculate the plasma insulin concentration that results in a 50% suppression of lipolysis. In obesity, insulin's action on adipose tissue lipolysis is clearly impaired, resulting in excess free fatty acids in circulation, which can lead to metabolic dysfunction. However, the cause of this impairment is unclear. The chronic, low-grade adipose tissue inflammation seen in obesity was thought to be the cause of adipose tissue insulin resistance. In this review, we discuss the structure of adipose tissue, how normal and abnormal adipose tissue metabolism contributes to metabolic diseases, and how inflammation might or might not play a role in adipose tissue insulin resistance.
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Affiliation(s)
- Shuhao Lin
- Endocrine Research Unit, Mayo Clinic, Rochester, MN, USA
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Lee H, Jun BG, Kim SH, Lee CH, Lim Y. Effects of Bioconverted Guava Leaf ( Psidium guajava L.) Extract on Skeletal Muscle Damage by Regulation of Ubiquitin-Proteasome System and Apoptosis in Type 2 Diabetic Mice. Int J Mol Sci 2025; 26:3877. [PMID: 40332596 PMCID: PMC12027545 DOI: 10.3390/ijms26083877] [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: 03/14/2025] [Revised: 04/11/2025] [Accepted: 04/17/2025] [Indexed: 05/08/2025] Open
Abstract
Skeletal muscle atrophy is one of the serious complications of diabetes, which increases the risk of frailty, falls, and mortality. However, interventions for muscle atrophy are limited, and research is needed regarding the treatment of muscle wasting. Recently, the bioconversion of natural products by lactic acid bacteria has been highlighted as a possibility to improve the bioavailability of active ingredients. This process also produces metabolites, which are key signaling mediators for a variety of physiological functions. This study investigated the effect of bioconverted guava leaf (Psidium guajava L., GL) by Lactobacillus plantarum on hyperglycemia-induced skeletal muscle atrophy in type 2 diabetes mellites (T2DM) mice. Diabetes was induced by a high-fat diet with a two-time streptozotocin (STZ) injection (60 mg/kg BW) in male C57BL/6J mice. After diabetes was induced (a fasting blood glucose level (FBG) ≥ 300 mg/dL), the mice were administered with GL (100 mg/kg/day) or bioconverted GL (FGL) (50 mg/kg/day) by oral gavage for 14 weeks. FGL contains different substances such as hydroxyl-isocaproic acid and hydroxyl-isovaleric acid compared to GLE itself, which have potential to prevent muscle degradation in T2DM mice. GL and FGL supplementation reduced the FBG level in T2DM mice. In addition, GL and FGL supplementation enhanced muscle strength, the skeletal muscle cross-sectional area, and ameliorated ubiquitin-proteasome system (UPS)-related pathways in T2DM mice. On the other hand, GLE supplementation ameliorated glucose tolerance demonstrated by oral glucose tolerance test and enhanced insulin signaling pathway. In addition, only FGL supplementation attenuated skeletal muscle inflammation and apoptosis with an improved mammalian target of the rapamycin (mTOR)-autophagy-related pathway. Although administered at a half dose of GLE, FGL demonstrated greater efficacy in regulating the expression of these molecular markers. The result suggests that even GL itself has anti-diabetic effects, and the functionality would be enhanced by the bioconversion of GL with L. Plantarum, which has an additive or/and a synergistic effect. Taken together, FGL could be used as a potential nutraceutical to attenuate muscle degradation by the inhibition of inflammation, the UPS, and the apoptosis pathway.
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MESH Headings
- Animals
- Psidium/chemistry
- Muscle, Skeletal/drug effects
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Male
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/pathology
- Mice
- Proteasome Endopeptidase Complex/metabolism
- Plant Extracts/pharmacology
- Plant Extracts/chemistry
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/complications
- Apoptosis/drug effects
- Plant Leaves/chemistry
- Ubiquitin/metabolism
- Muscular Atrophy/drug therapy
- Muscular Atrophy/metabolism
- Muscular Atrophy/etiology
- Muscular Atrophy/pathology
- Mice, Inbred C57BL
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Affiliation(s)
- Heaji Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Bo-Gyu Jun
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; (B.-G.J.); (S.-H.K.); (C.H.L.)
| | - Su-Hyun Kim
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; (B.-G.J.); (S.-H.K.); (C.H.L.)
| | - Choong Hwan Lee
- Department of Bioscience and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; (B.-G.J.); (S.-H.K.); (C.H.L.)
- Research Institute for Bioactive-Metabolome Network, Konkuk University, Seoul 05029, Republic of Korea
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea;
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Zhang Y, Tang Y, Xu L, Fang L, Li X, Mao W, Liu T. Effect of limb ischemic preconditioning on the indirect index of insulin resistance in maintenance hemodialysis patients. BMC Cardiovasc Disord 2025; 25:238. [PMID: 40158091 PMCID: PMC11954303 DOI: 10.1186/s12872-025-04677-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 03/17/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Poor prognosis of maintenance hemodialysis (MHD) patients, including cardiovascular disease (CVD) and protein-energy wasting (PEW), is strongly associated with insulin resistance (IR). Previous studies have revealed that limb ischemic preconditioning (LIPC), as an intervention, is effective in reducing inflammation and oxidative stress levels in patients. The aim of this study was to elucidate the effects of LIPC on IR indirect indices, inflammation and oxidative stress indices, and to further explore the potential mechanisms of LIPC in reducing IR indices. METHODS A retrospective analysis was performed on 62 patients with MHD who had previously undergone limb ischemia preconditioning (LIPC) or sham surgery (Sham). General clinical and laboratory data were collected. Furthermore, to assess the IR status of MHD patients, the following indices were employed: triglyceride-glucose index (TyG), triglyceride-glucose body mass index (TyG-BMI), triglyceride-to-high-density lipoprotein cholesterol ratio (TG/HDL-C), and metabolic score of insulin resistance (METS-IR). Inflammation and oxidative stress indicators included high-sensitivity C-reactive protein (hs-CRP), hs-CRP /albumin ratio (CAR), serum malondialdehyde (MDA) and superoxide dismutase (SOD). Mediation analysis was conducted using Model 4 in the SPSS PROCESS macro version 4.1. RESULTS Following a four-week experiment, hs-CRP (15.46 ± 3.60 vs. 10.53 ± 5.42, p < 0.001), CAR (0.39 ± 0.10 vs. 0.26 ± 0.13, p < 0.001) and MDA (8.46(6.71,9.85) vs. 5.99(5.11,7.89), p = 0.001) indices were significantly decreased in the MHD patients of the LIPC group, whereas SOD indices (215.07(180.27,286.45) vs. 267.76(228.32,319.54), p = 0.012) were significantly higher. Only hs-CRP (-4.93 ± 5.68 vs. 0.16 ± 5.39, p = 0.001) and CAR (-0.14 ± 0.14 vs. -0.001 ± 0.15, p = 0.001) were significantly different in the LIPC group compared to the Sham group. In contrast, the changes in MDA (p = 0.058) and SOD (p = 0.107) were not statistically significant between groups. The intra- and inter-group differences in the four indirect indices of IR were significant (p < 0.05). The heatmap revealed a notable correlation between the changes in hs-CRP and CAR levels and the changes in the IR indirect indices. In addition, The mediation model showed that the inflammatory indicators hs-CRP played a partial mediating role in the improvement of IR indices (TyG-BMI) by LIPC. CONCLUSION LIPC has an excellent ability to inhibit inflammation and peroxidation. In addition, in MHD patients, inflammation plays a significant role in the process of LIPC improving IR index.
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Affiliation(s)
- Yu Zhang
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Yushang Tang
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Linfang Xu
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Li Fang
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Xiaoping Li
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Wenbin Mao
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China
| | - Tongqiang Liu
- Department of Nephrology, The Second People's Hospital of Changzhou, Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China.
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Habobe HA, Pieters RHH, Bikker FJ. Investigating the Salivary Biomarker Profile in Obesity: A Systematic Review. Curr Obes Rep 2025; 14:25. [PMID: 40153192 PMCID: PMC11953185 DOI: 10.1007/s13679-025-00618-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/11/2025] [Indexed: 03/30/2025]
Abstract
PURPOSE OF REVIEW This systematic review aims to map the existing literature on salivary biomarkers in adults with metabolically unhealthy obesity (MUO), identify key biomarkers associated with this high-risk group, and highlight areas requiring further research to advance this emerging field. RECENT FINDINGS Obesity is characterized by an abnormal accumulation of body fat and chronic inflammation. However, not all individuals with obesity experience metabolic dysfunction. This review focuses on MUO, which is strongly linked to metabolic disorders such as insulin resistance, cardiovascular disease, type 2 diabetes, and systemic inflammation. Linking MUO and salivary biomarkers may enhance our understanding of how systemic health influences salivary composition and could enable the early identification of high-risk individuals through non-invasive saliva testing. This review synthesized findings from recent studies and identified key salivary biomarkers consistently elevated in individuals with MUO, including 8-OHdG, IL-6, IL-8, resistin, TNFR1, PTX-3, AEA, OEA, TNF-α, and sICAM-1. These biomarkers are associated with inflammation, oxidative stress, and metabolic dysregulation. The majority of studies utilized cross-sectional designs and used various saliva collection methods. Salivary biomarkers hold promise as non-invasive indicators of obesity-related metabolic dysfunction, particularly in MUO. However, their clinical diagnostic utility remains uncertain due to heterogeneity in study designs, a lack of biomarker validation, and limited longitudinal studies. Further research is needed to establish their bona fide diagnostic potential.
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Affiliation(s)
- H Al Habobe
- Research Group Innovative Testing in Life Sciences and Chemistry, Research Centre for Healthy and Sustainable Living, University of Applied Sciences Utrecht, Utrecht, The Netherlands.
- Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands.
| | - R H H Pieters
- Research Group Innovative Testing in Life Sciences and Chemistry, Research Centre for Healthy and Sustainable Living, University of Applied Sciences Utrecht, Utrecht, The Netherlands
- Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - F J Bikker
- Department of Oral Biochemistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Amsterdam, The Netherlands
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10
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Lin S, Cienfuegos S, Ezpeleta M, Pavlou V, Corapi S, Runchey MC, Alexandria SJ, Tussing-Humphreys L, Varady KA. Time-Restricted Eating Versus Daily Calorie Restriction: Effects on Inflammatory Markers over 12 Months in Adults with Obesity. Nutrients 2025; 17:1130. [PMID: 40218888 PMCID: PMC11990601 DOI: 10.3390/nu17071130] [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: 03/03/2025] [Revised: 03/19/2025] [Accepted: 03/21/2025] [Indexed: 04/14/2025] Open
Abstract
Background/Objectives: Obesity is associated with chronic systemic inflammation and elevated levels of inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and C-reactive protein (CRP). Weight loss through lifestyle interventions can reduce inflammation in adults with obesity. Time-restricted eating (TRE) and calorie restriction (CR) are two popular diet interventions that can produce clinically significant weight loss. However, to date, no studies have directly compared the effects of TRE versus CR on inflammatory cytokines in adults with obesity. Methods: Here, we performed a secondary analysis on a recently published study to compare the long-term (12-month) effects of TRE versus CR on key inflammatory cytokines. Results: We found that while TRE and CR produced similar amounts of weight loss (4-5% from baseline), no statistically significant changes in circulating levels of TNF-alpha, IL-6, and CRP were noted in the TRE or CR groups, compared to the controls, by month 12. However, we did observe that circulating CRP levels were positively related to body weight, visceral fat mass, and insulin resistance, while IL-6 and TNF-alpha were not related to any metabolic marker. Conclusions: Thus, TRE and CR may not affect key inflammatory mediators with 4-5% weight loss, but more research is warranted.
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Affiliation(s)
- Shuhao Lin
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Sofia Cienfuegos
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Mark Ezpeleta
- Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO 80045, USA;
| | - Vasiliki Pavlou
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Sarah Corapi
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Mary-Claire Runchey
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Shaina J. Alexandria
- Department of Preventative Medicine (Biostatistics), Northwestern University, Chicago, IL 60208, USA;
| | - Lisa Tussing-Humphreys
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
| | - Krista A. Varady
- Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL 60607, USA; (S.L.); (S.C.); (V.P.); (S.C.); (M.-C.R.); (L.T.-H.)
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11
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Mittal R, Prasad K, Lemos JRN, Arevalo G, Hirani K. Unveiling Gestational Diabetes: An Overview of Pathophysiology and Management. Int J Mol Sci 2025; 26:2320. [PMID: 40076938 PMCID: PMC11900321 DOI: 10.3390/ijms26052320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/14/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women.
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Affiliation(s)
| | | | | | | | - Khemraj Hirani
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (K.P.); (J.R.N.L.); (G.A.)
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12
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Langlois A, Cherfan J, Meugnier E, Rida A, Arous C, Peronet C, Hamdard H, Zarrouki B, Wehrle‐Haller B, Pinget M, Craige SM, Bouzakri K. DECORIN, a triceps-derived myokine, protects sorted β-cells and human islets against chronic inflammation associated with type 2 diabetes. Acta Physiol (Oxf) 2025; 241:e14267. [PMID: 39844653 PMCID: PMC11754997 DOI: 10.1111/apha.14267] [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: 09/05/2024] [Revised: 11/28/2024] [Accepted: 01/01/2025] [Indexed: 01/24/2025]
Abstract
AIM Pancreatic β-cells are susceptible to inflammation, leading to decreased insulin production/secretion and cell death. Previously, we have identified a novel triceps-derived myokine, DECORIN, which plays a pivotal role in skeletal muscle-to-pancreas interorgan communication. However, whether DECORIN can directly impact β-cell function and susceptibility to inflammation remains unexplored. METHODS The effect of DECORIN was assessed in sorted human and rat β-cell and human islets from healthy and type 2 diabetes (T2D) donors. We assessed glucose-stimulated insulin secretion (GSIS) and cytokine-mediated cell death. We then challenged sorted β-cells and human islets with inflammatory cytokines commonly associated with diabetes, such as tumor necrosis factor-α (TNF-α) alone or in combination with interleukin1-β (IL1-β) and interferon-γ (cytomix). RESULTS DECORIN enhanced cell spreading and the localization of phosphorylated FAK at adhesions, promoting GSIS under basal conditions. It also increased insulin granule docking adhesion length and countered the inhibitory effects of TNF-α on adhesion and actin remodeling at the β-cell surface, resulting in preserved GSIS. DECORIN protected from cell death in sorted β-cells and islets challenged with TNF-α alone or TNF-α + cytomix. Interestingly, DECORIN increased both insulin content and secretion in human islets from T2D individuals. Additionally, DECORIN treatment reversed the impaired gene expression caused by T2D and enhanced the expression of genes essential for islet function and metabolism. CONCLUSION Collectively, we have shown that DECORIN had a beneficial effect on human islets, protecting them from inflammation-induced cell death. In T2D islets, DECORIN restores islet function and reverses the expression of T2D-associated genes. Based on our data, we propose that DECORIN is a promising therapeutic target for diabetes-associated inflammation and diabetes itself.
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Affiliation(s)
- Allan Langlois
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
| | - Julien Cherfan
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
| | - Emmanuelle Meugnier
- CarMeN Laboratory, Inserm U1060, INRAE UMR1397, Univ‐LyonUniversité Claude Bernard Lyon‐1LyonFrance
| | - Ahmad Rida
- ILONOV, Boulevard René LericheStrasbourgFrance
| | - Caroline Arous
- Department of Cell Physiology and Metabolism, Centre Médical UniversitaireUniversity of GenevaGenevaSwitzerland
| | - Claude Peronet
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
| | - Harzo Hamdard
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
| | - Bader Zarrouki
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolic (CVRM), BioPharmaceuticals R&DGothenburgSweden
| | - Bernhard Wehrle‐Haller
- Department of Cell Physiology and Metabolism, Centre Médical UniversitaireUniversity of GenevaGenevaSwitzerland
| | - Michel Pinget
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
- ILONOV, Boulevard René LericheStrasbourgFrance
| | - Siobhan M. Craige
- Department of Human Nutrition, Foods, and ExerciseVirginia TechBlacksburgVirginiaUSA
| | - Karim Bouzakri
- UR Diabète et Thérapeutiques, Centre européen d'étude du DiabèteUniversité de StrasbourgStrasbourgFrance
- ILONOV, Boulevard René LericheStrasbourgFrance
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13
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Wang M, Wang P, Liu Y, Chen C, Zhi Z, Wang Y, Liu F, Zhao L. Stress hyperglycemia ratio is associated with delayed cerebrovascular ischemia and poor prognosis in patients with aneurysmal subarachnoid hemorrhage undergoing neurointerventional therapy. Clin Neurol Neurosurg 2025; 249:108769. [PMID: 39921965 DOI: 10.1016/j.clineuro.2025.108769] [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: 10/14/2024] [Revised: 01/23/2025] [Accepted: 01/30/2025] [Indexed: 02/10/2025]
Abstract
OBJECTIVE Previous research has established a correlation between hyperglycemia following aneurysmal subarachnoid hemorrhage (aSAH) and the onset of delayed cerebrovascular ischemia (DCI), and influencing patient prognosis. The objective of this study was to evaluate the potential association between stress hyperglycemia ratio (SHR) and both the occurrence of DCI and prognosis in patients with aSAH undergoing neurointervention. METHODS We retrospectively analyzed 214 patients with aSAH undergoing neurointervention. The outcomes evaluated were DCI and 90-days poor prognosis (Modified Rankin Scale, mRS >2). The association between SHR level and both DCI and prognosis was analyzed. Stress hyperglycemia was assessed using SHR, calculated as: SHR = admission fasting plasma glucose (FPG, mmol/L) / [1.59 * hemoglobin A1c (HbA1c%) - 2.59]. RESULTS Among the 214 patients, 59 (27.6 %) experienced DCI, and 60 (28 %) had a poor prognosis. Following adjustments for confounding factors, SHR emerged as an independent risk factor of both DCI (p = 0.006) and poor prognosis (p = 0.020), individuals in the T3 tertile of SHR had a higher risk of DCI than those in the T1 tertile [odds ratio (OR) 2.68; 95 % CI (1.19-6.06); p = 0.018], and individuals in the T3 tertile of SHR had a higher risk of poor 90-day prognosis than those in the T1 tertile [OR 2.47; 95 % CI (1.08-5.63); p = 0.032]. CONCLUSION SHR was found to be a significant and independent risk factor for DCI and 90-days poor prognosis in patients with aSAH who underwent neurointerventional therapy.
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Affiliation(s)
- Mengchao Wang
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Ping Wang
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Yufeng Liu
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Chun Chen
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Zhongwen Zhi
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Yuqian Wang
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Fan Liu
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
| | - Liandong Zhao
- Department of Neurology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, Jiangsu 223002, PR China.
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14
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Cho Y, Choi EY, Choi A, Han JY, Ye BD, Kim JH, Shin JY. Anti-Tumor Necrosis Factor Therapy and the Risk of Gestational Diabetes in Pregnant Women With Inflammatory Bowel Disease. Am J Gastroenterol 2025; 120:241-250. [PMID: 39315687 DOI: 10.14309/ajg.0000000000003100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 09/18/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION Anti-tumor necrosis factor (anti-TNF) therapy may improve insulin sensitivity, and its impact during pregnancy remains unclear. We aimed to assess the risk of gestational diabetes mellitus (GDM) associated with anti-TNF treatment among pregnant women with inflammatory bowel disease (IBD). METHODS This nationwide cohort study included patients with IBD in Korea from 2010 to 2021. Anti-TNF exposure was identified from the last menstrual period (LMP) to LMP + 140 days. The development of GDM was assessed from LMP + 141 days to delivery. We performed overlap weighting to balance the covariates and used a generalized linear mixed model to measure the risk ratio (RR) and 95% confidence intervals (CIs). The anti-TNF group was compared with the unexposed group, as well as with the immunosuppressant, 5-aminosalicylate, and untreated groups. RESULTS A total of 3,695 pregnancies in women with IBD were identified, of which 338 (9.2%) were exposed to anti-TNFs. GDM was found in 7.1% of the pregnancies exposed to anti-TNFs as compared with 11.0% of those unexposed. The crude and weighted RRs for GDM risk were 0.64 (95% CI 0.43-0.96) and 0.68 (95% CI 0.55-0.84), respectively. The weighted RR when compared with the immunosuppressant, 5-aminosalicylate, and untreated groups was 0.70 (95% CI 0.41-1.18), 0.71 (95% CI 0.52-0.95), and 0.85 (95% CI 0.59-1.24), respectively. DISCUSSION This nationwide cohort reported a decreased risk of GDM among patients who used anti-TNFs during early pregnancy compared with those unexposed. GDM risk may become a consideration in the decision-making process when choosing treatment options for pregnant women with a risk factor for GDM.
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Affiliation(s)
- Yongtai Cho
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Eun-Young Choi
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
| | - Ahhyung Choi
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
- Harvard-MIT Center for Regulatory Science, Harvard Medical School, Boston, Massachusetts, USA
| | - Jung Yeol Han
- Korea Mothersafe Counseling Center, Department of Obstetrics and Gynecology, Inje University Ilsan Paik Hospital, Goyang, South Korea
| | - Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ju Hwan Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea
| | - Ju-Young Shin
- School of Pharmacy, Sungkyunkwan University, Suwon, South Korea
- Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea
- Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea
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15
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Hansman DS, Du J, Casson RJ, Peet DJ. Eye on the horizon: The metabolic landscape of the RPE in aging and disease. Prog Retin Eye Res 2025; 104:101306. [PMID: 39433211 PMCID: PMC11833275 DOI: 10.1016/j.preteyeres.2024.101306] [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: 08/29/2024] [Revised: 10/10/2024] [Accepted: 10/10/2024] [Indexed: 10/23/2024]
Abstract
To meet the prodigious bioenergetic demands of the photoreceptors, glucose and other nutrients must traverse the retinal pigment epithelium (RPE), a polarised monolayer of cells that lie at the interface between the outer retina and the choroid, the principal vascular layer of the eye. Recent investigations have revealed a metabolic ecosystem in the outer retina where the photoreceptors and RPE engage in a complex exchange of sugars, amino acids, and other metabolites. Perturbation of this delicate metabolic balance has been identified in the aging retina, as well as in age-related macular degeneration (AMD), the leading cause of blindness in the Western world. Also common in the aging and diseased retina are elevated levels of cytokines, oxidative stress, advanced glycation end-products, increased growth factor signalling, and biomechanical stress - all of which have been associated with metabolic dysregulation in non-retinal cell types and tissues. Herein, we outline the role of these factors in retinal homeostasis, aging, and disease. We discuss their effects on glucose, mitochondrial, lipid, and amino acid metabolism in tissues and cell types outside the retina, highlighting the signalling pathways through which they induce these changes. Lastly, we discuss promising avenues for future research investigating the roles of these pathological conditions on retinal metabolism, potentially offering novel therapeutic approaches to combat age-related retinal disease.
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Affiliation(s)
- David S Hansman
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia.
| | - Jianhai Du
- Department of Ophthalmology and Visual Sciences, Department of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA
| | - Robert J Casson
- Discipline of Ophthalmology and Visual Science, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Daniel J Peet
- School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia
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16
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Olotu T, Ferrell JM. Lactobacillus sp. for the Attenuation of Metabolic Dysfunction-Associated Steatotic Liver Disease in Mice. Microorganisms 2024; 12:2488. [PMID: 39770690 PMCID: PMC11728176 DOI: 10.3390/microorganisms12122488] [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: 09/20/2024] [Revised: 11/19/2024] [Accepted: 11/26/2024] [Indexed: 01/05/2025] Open
Abstract
Probiotics are studied for their therapeutic potential in the treatment of several diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). Part of the significant progress made in understanding the pathogenesis of steatosis has come from identifying the complex interplay between the gut microbiome and liver function. Recently, probiotics have shown beneficial effects for the treatment and prevention of steatosis and MASLD in rodent models and in clinical trials. Numerous studies have demonstrated the promising potential of lactic acid bacteria, especially the genus Lactobacillus. Lactobacillus is a prominent bile acid hydrolase bacterium that is involved in the biotransformation of bile acids. This genus' modulation of the gut microbiota also contributes to overall gut health; it controls gut microbial overgrowth, shapes the intestinal bile acid pool, and alleviates inflammation. This narrative review offers a comprehensive summary of the potential of Lactobacillus in the gut-liver axis to attenuate steatosis and MASLD. It also highlights the roles of Lactobacillus in hepatic lipid metabolism, insulin resistance, inflammation and fibrosis, and bile acid synthesis in attenuating MASLD.
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Affiliation(s)
- Titilayo Olotu
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
| | - Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA;
- School of Biomedical Sciences, Kent State University, Kent, OH 44242, USA
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17
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Wagner R, Buettner J, Heni M, Fritsche L, Kullmann S, Wagmüller M, Peter A, Preissl H, Machann J, Jumpertz von Schwartzenberg R, Birkenfeld AL, Pape UF, van Hall G, Plomgaard P, Häring HU, Fritsche A, Thompson KN, Klein R, Stefan N. Carrageenan and insulin resistance in humans: a randomised double-blind cross-over trial. BMC Med 2024; 22:558. [PMID: 39593091 PMCID: PMC11590543 DOI: 10.1186/s12916-024-03771-8] [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: 06/09/2024] [Accepted: 11/13/2024] [Indexed: 11/28/2024] Open
Abstract
BACKGROUND The potential impact of specific food additives, common in Western diets, on the risk of developing type 2 diabetes is not well understood. This study focuses on carrageenan, a widely used food additive known to induce insulin resistance and gut inflammation in animal models, and its effects on human health. METHODS In a randomised, double-blind, placebo-controlled, cross-over trial conducted at a university hospital metabolic study centre, 20 males (age 27.4 ± 4.3 years, BMI 24.5 ± 2.5 kg/m2) participated. The intervention involved oral intake of carrageenan (250 mg) or placebo in the morning and in the evening and each intervention lasted 2 weeks. The primary outcome measured was insulin sensitivity (using oral glucose tolerance test [OGTT] and hyperinsulinaemic-euglycaemic clamp). Additional end-points included whole body and hepatic insulin sensitivity, MRI-measured brain inflammation and insulin resistance, intestinal permeability (via lactulose-mannitol test and plasma zonulin levels), and gut microbiome composition. Immune-cell activation and pro-inflammatory cytokine release from peripheral blood mononuclear cells were measured. RESULTS Overall insulin sensitivity did not show significant differences between the treatments. However, interactions between BMI and treatment were observed (OGTT-based insulin sensitivity index: p=0.04, fasting insulin resistance: p=0.01, hepatic insulin sensitivity index: p=0.04). In overweight participants, carrageenan exposure resulted in lower whole body and hepatic insulin sensitivity, a trend towards increased brain inflammation, and elevated C-reactive protein (CRP) and IL-6 levels compared to placebo. Additionally, carrageenan was associated with increased intestinal permeability. In vitro natural killer (NK-)cell activation and increased pro-inflammatory cytokine release were found after carrageenan exposure in the participant's peripheral blood mononuclear cells. CONCLUSIONS These findings suggest that carrageenan, a common food additive, may contribute to insulin resistance and subclinical inflammation in overweight individuals through pro-inflammatory mechanisms in the gut. Further investigation into the long-term health impacts of carrageenan and other food additives is warranted. TRIAL REGISTRATION NCT02629705.
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Affiliation(s)
- Robert Wagner
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich Heine University, Moorenstr 5, Düsseldorf, 40225, Germany.
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany.
- Department of Biostatistics, Microbiome Analysis Core, Harvard T.H. Chan School of Public Health, Boston, USA.
| | - Janine Buettner
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, Berlin, Germany
| | - Martin Heni
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Louise Fritsche
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Stephanie Kullmann
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Moritz Wagmüller
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Andreas Peter
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Hubert Preissl
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
- Institute of Pharmaceutical Sciences, Department of Pharmacy and Biochemistry; Interfaculty Centre for Pharmacogenomics and Pharma Research at the Eberhard Karls University Tübingen, Tübingen, Germany
| | - Jürgen Machann
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Section On Experimental Radiology, Department of Diagnostic and Interventional Radiology, University Hospital of Tübingen, Tübingen, Germany
| | - Reiner Jumpertz von Schwartzenberg
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Ulrich-Frank Pape
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin, Berlin, Germany
- Department of Internal Medicine and Gastroenterology, Asklepios Klinik St. Georg, Hamburg, Germany
| | - Gerrit van Hall
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Peter Plomgaard
- Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
| | - Hans-Ulrich Häring
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Andreas Fritsche
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Kelsey N Thompson
- Department of Biostatistics, Microbiome Analysis Core, Harvard T.H. Chan School of Public Health, Boston, USA
| | - Reinhild Klein
- Department of Internal Medicine II, Division of Haematology, Oncology, Immunology and Rheumatology, University Hospital of Tübingen, Tübingen, Germany
| | - Norbert Stefan
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital of Tübingen, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
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18
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Torres-Torres J, Monroy-Muñoz IE, Perez-Duran J, Solis-Paredes JM, Camacho-Martinez ZA, Baca D, Espino-Y-Sosa S, Martinez-Portilla R, Rojas-Zepeda L, Borboa-Olivares H, Reyes-Muñoz E. Cellular and Molecular Pathophysiology of Gestational Diabetes. Int J Mol Sci 2024; 25:11641. [PMID: 39519193 PMCID: PMC11546748 DOI: 10.3390/ijms252111641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 10/25/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Gestational diabetes (GD) is a metabolic disorder characterized by glucose intolerance during pregnancy, significantly impacting maternal and fetal health. Its global prevalence is approximately 14%, with risk factors including obesity, family history of diabetes, advanced maternal age, and ethnicity, which are linked to cellular and molecular disruptions in glucose regulation and insulin resistance. GD is associated with short- and long-term complications for both the mother and the newborn. For mothers, GD increases the risk of developing type 2 diabetes, cardiovascular diseases, and metabolic syndrome. In the offspring, exposure to GD in utero predisposes them to obesity, glucose intolerance, and metabolic disorders later in life. This review aims to elucidate the complex cellular and molecular mechanisms underlying GD to inform the development of effective therapeutic strategies. A systematic review was conducted using medical subject headings (MeSH) terms related to GD's cellular and molecular pathophysiology. Inclusion criteria encompassed original studies, systematic reviews, and meta-analyses focusing on GD's impact on maternal and fetal health, adhering to PRISMA guidelines. Data extraction captured study characteristics, maternal and fetal outcomes, key findings, and conclusions. GD disrupts insulin signaling pathways, leading to impaired glucose uptake and insulin resistance. Mitochondrial dysfunction reduces ATP production and increases reactive oxygen species, exacerbating oxidative stress. Hormonal influences, chronic inflammation, and dysregulation of the mammalian target of rapamycin (mTOR) pathway further impair insulin signaling. Gut microbiota alterations, gene expression, and epigenetic modifications play significant roles in GD. Ferroptosis and placental dysfunction primarily contribute to intrauterine growth restriction. Conversely, fetal macrosomia arises from maternal hyperglycemia and subsequent fetal hyperinsulinemia, resulting in excessive fetal growth. The chronic inflammatory state and oxidative stress associated with GD exacerbate these complications, creating a hostile intrauterine environment. GD's complex pathophysiology involves multiple disruptions in insulin signaling, mitochondrial function, inflammation, and oxidative stress. Effective management requires early detection, preventive strategies, and international collaboration to standardize care and improve outcomes for mothers and babies.
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Affiliation(s)
- Johnatan Torres-Torres
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
- Obstetric and Gynecology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City 06720, Mexico
| | - Irma Eloisa Monroy-Muñoz
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
| | - Javier Perez-Duran
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
| | - Juan Mario Solis-Paredes
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
| | | | - Deyanira Baca
- Obstetric and Gynecology Department, Hospital General de México Dr. Eduardo Liceaga, Mexico City 06720, Mexico
| | - Salvador Espino-Y-Sosa
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
- Centro de Investigacion en Ciencias de la Salud, Universidad Anahuac Mexico, Campus Norte, Huixquilucan 52786, Mexico
| | - Raigam Martinez-Portilla
- Department of Reproductive and Perinatal Health Research, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
| | - Lourdes Rojas-Zepeda
- Maternal-Fetal Department, Instituto Materno Infantil del Estado de Mexico, Toluca 50170, Mexico
| | - Hector Borboa-Olivares
- Community Interventions Research Branch, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
| | - Enrique Reyes-Muñoz
- Research Division, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, Mexico City 11000, Mexico
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19
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Weinberg Sibony R, Segev O, Dor S, Raz I. Overview of oxidative stress and inflammation in diabetes. J Diabetes 2024; 16:e70014. [PMID: 39435991 PMCID: PMC11494684 DOI: 10.1111/1753-0407.70014] [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: 09/06/2024] [Accepted: 09/10/2024] [Indexed: 10/23/2024] Open
Abstract
The global prevalence of diabetes has increased significantly, leading to various complications and a negative impact on quality of life. Hyperglycemia hyperglycemic-induced oxidative stress (OS) and inflammation are closely associated with the development and progression of type 2 diabetes mellitus (T2D) and its complications. This review explores the effect of T2D on target organ damage and potential treatments to minimize this damage. The paper examines the pathophysiology of T2D, focusing on low-grade chronic inflammation and OS and on their impact on insulin resistance. The review discusses the role of inflammation and OS in the development of microvascular and macrovascular complications. The findings highlight the mechanisms by which inflammatory cytokines, stress kinases, and reactive oxygen species (ROS) interfere with insulin signaling pathways, leading to impaired glucose metabolism and organ dysfunction. Lifestyle interventions, including a balanced diet and exercise, can help reduce chronic inflammation and OS, thereby preventing and controlling T2D and its associated complications. Additionally, various antioxidants and anti-inflammatory agents show potential in reducing OS and inflammation. Some anti-diabetic drugs, like pioglitazone, metformin, and glucagon-like peptide-1 (GLP-1) agonists, may also have anti-inflammatory effects. Further research, including randomized controlled trials, is needed to evaluate the efficacy of these interventions.
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Affiliation(s)
| | - Omri Segev
- Faculty of MedicineTel Aviv UniversityTel AvivIsrael
| | - Saar Dor
- Faculty of MedicineBen‐Gurion University of the NegevBeer ShevaIsrael
| | - Itamar Raz
- Faculty of MedicineHebrew University of JerusalemJerusalemIsrael
- Diabetes Unit, Department of Endocrinology and MetabolismHadassah Medical CenterJerusalemIsrael
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20
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Yadav M, Verma S, Tiwari P, Mugale MN. Unraveling the mechanisms of hepatogenous diabetes and its therapeutic perspectives. Life Sci 2024; 353:122934. [PMID: 39089644 DOI: 10.1016/j.lfs.2024.122934] [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: 05/09/2024] [Revised: 06/26/2024] [Accepted: 07/25/2024] [Indexed: 08/04/2024]
Abstract
The review focused mainly on the pathogenesis of hepatogenous diabetes (HD) in liver cirrhosis (LC). This review reveals parallels between the mechanisms of metabolic dysfunction observed in LC and type II diabetes (T2DM), suggesting a shared pathway leading to HD. It underscores the role of insulin in HD pathogenesis, highlighting key factors such as insulin signaling, glucose metabolism, insulin resistance (IR), and the influence of adipocytes. Furthermore, the impact of adipose tissue accumulation, fatty acid metabolism, and pro-inflammatory cytokines like Tumor necrosis factor-α (TNF-α) on IR are discussed in the context of HD. Altered signaling pathways, disruptions in the endocrine system, liver inflammation, changes in muscle mass and composition, and modifications to the gut microbiota collectively contribute to the complex interplay linking cirrhosis and HD. This study highlights how important it is to identify and treat this complex condition in cirrhotic patients by thoroughly analyzing the link between cirrhosis, IR, and HD. It also emphasizes the vitality of targeted interventions. Cellular and molecular investigations into IR have revealed potential therapeutic targets for managing and preventing HD.
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Affiliation(s)
- Manisha Yadav
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Verma
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Purnima Tiwari
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India
| | - Madhav Nilakanth Mugale
- Division of Toxicology and Experimental Medicine, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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21
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Hoffmann SW, Schierbauer J, Zimmermann P, Voit T, Grothoff A, Wachsmuth NB, Rössler A, Niedrist T, Lackner HK, Moser O. Effects of Interrupting Prolonged Sitting with Light-Intensity Physical Activity on Inflammatory and Cardiometabolic Risk Markers in Young Adults with Overweight and Obesity: Secondary Outcome Analyses of the SED-ACT Randomized Controlled Crossover Trial. Biomolecules 2024; 14:1029. [PMID: 39199416 PMCID: PMC11352707 DOI: 10.3390/biom14081029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/16/2024] [Accepted: 08/18/2024] [Indexed: 09/01/2024] Open
Abstract
Sedentary behavior (SB) is an essential risk factor for obesity, cardiovascular disease, and type 2 diabetes. Though certain levels of physical activity (PA) may attenuate the detrimental effects of SB, the inflammatory and cardiometabolic responses involved are still not fully understood. The focus of this secondary outcome analysis was to describe how light-intensity PA snacks (LIPASs, alternate sitting and standing, walking or standing continuously) compared with uninterrupted prolonged sitting affect inflammatory and cardiometabolic risk markers. Seventeen young adults with overweight and obesity participated in this study (eight females, 23.4 ± 3.3 years, body mass index (BMI) 29.7 ± 3.8 kg/m2, glycated hemoglobin A1C (HbA1c) 5.4 ± 0.3%, body fat 31.8 ± 8.2%). Participants were randomly assigned to the following conditions which were tested during an 8 h simulated workday: uninterrupted prolonged sitting (SIT), alternate sitting and standing (SIT-STAND, 2.5 h total standing time), continuous standing (STAND), and continuous walking (1.6 km/h; WALK). Each condition also included a standardized non-relativized breakfast and lunch. Venous blood samples were obtained in a fasted state at baseline (T0), 1 h after lunch (T1) and 8 h after baseline (T2). Inflammatory and cardiometabolic risk markers included interleukin-6 (IL-6), c-reactive protein (CRP), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), visceral fat area (VFA), triglyceride-glucose (TyG) index, two lipid ratio measures, TG/HDL-C and TC/HDL-C, albumin, amylase (pancreatic), total protein, uric acid, and urea. We found significant changes in a broad range of certain inflammatory and cardiometabolic risk markers during the intervention phase for IL-6 (p = 0.014), TG (p = 0.012), TC (p = 0.017), HDL-C (p = 0.020), LDL-C (p = 0.021), albumin (p = 0.003), total protein (p = 0.021), and uric acid (p = 0.040) in favor of light-intensity walking compared with uninterrupted prolonged sitting, alternate sitting and standing, and continuous standing. We found no significant changes in CRP (p = 0.529), creatinine (p = 0.199), TyG (p = 0.331), and the lipid ratios TG/HDL-C (p = 0.793) and TC/HDL-C (p = 0.221) in response to the PA snack. During a simulated 8 h work environment replacement and interruption of prolonged sitting with light-intensity walking, significant positive effects on certain inflammatory and cardiometabolic risk markers were found in young adults with overweight and obesity.
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Affiliation(s)
- Sascha W. Hoffmann
- Division of Theory and Practice of Sports and Fields of Physical Activity, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany
| | - Janis Schierbauer
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
| | - Paul Zimmermann
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
| | - Thomas Voit
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
| | - Auguste Grothoff
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
| | - Nadine B. Wachsmuth
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
| | - Andreas Rössler
- Department of Physiology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria; (A.R.); (H.K.L.)
| | - Tobias Niedrist
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8010 Graz, Austria;
| | - Helmut K. Lackner
- Department of Physiology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria; (A.R.); (H.K.L.)
| | - Othmar Moser
- Division of Exercise Physiology and Metabolism, BaySpo—Bayreuth Center of Sport Science, University of Bayreuth, 95440 Bayreuth, Germany; (J.S.); (P.Z.); (T.V.); (A.G.); (N.B.W.)
- Interdisciplinary Metabolic Medicine Trials Unit, Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, 8010 Graz, Austria
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22
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Yu Y, Tan T, Yang W, Xu Z, Liu Y. Association between the systemic immune-inflammation index and obesity among adults: Insights from the NHANES 2017-2018. PLoS One 2024; 19:e0308288. [PMID: 39116149 PMCID: PMC11309425 DOI: 10.1371/journal.pone.0308288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 07/21/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Inflammation is an important causative factor of obesity. This study aimed to explore the possible association between the systemic immune-inflammatory index, a novel indicator of inflammation, and obesity. METHODS Data were collected from 4395 participants of the National Health and Nutrition Examination Survey 2017-2018 aged ≥ 20 years. The systemic immune-inflammatory index was calculated by multiplying the platelet count by the neutrophil-to-lymphocyte ratio. Obesity was defined as a body mass index ≥ 30 kg/m2. RESULTS A significant positive correlation was observed between the systemic immune-inflammatory index and body mass index following multivariate linear regression analysis (β = 1.75; 95% confidence interval = 1.16-2.33), which was greatest in adults aged < 60 years without hypertension and diabetes. Smoothed curve fitting and threshold effect analysis were used to characterize the nonlinear association between the systemic immune-inflammatory index and body mass index, and the inflection point was found to be 729.3. CONCLUSIONS The systemic immune-inflammatory index is positively associated with body mass index among adults in the United States and has the potential to enhance efforts to prevent adult obesity.
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Affiliation(s)
- Yanmei Yu
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Tongcai Tan
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wei Yang
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhitao Xu
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yong Liu
- Department of Rehabilitation Medicine, Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China
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23
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Caso F, Fatica M, Ferraioli M, Megna M, Potestio L, Ruggiero A, Tommasino N, Maione F, Scarpa R, Chimenti MS, Costa L. The role of bDMARDs in the prevention and treatment of inflammatory-related comorbidities in Psoriatic Arthritis. Expert Opin Biol Ther 2024; 24:719-731. [PMID: 39037828 DOI: 10.1080/14712598.2024.2384090] [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: 05/26/2024] [Accepted: 07/21/2024] [Indexed: 07/24/2024]
Abstract
INTRODUCTION Psoriatic arthritis (PsA) is an immune-inflammatory disease that affects both joints and entheses, and with diverse extra-articular manifestations (psoriasis, inflammatory bowel disease (IBD), and uveitis). A wide range of comorbid conditions, including cardiovascular diseases, obesity, metabolic syndrome (MetS), nonalcoholic fatty liver disease (NAFLD), mental health disorders (depression/anxiety), and osteoporosis are highly prevalent in course of PsA.Biological DMARDs (bDMARD), including TNF-inhibitors (TNFi), Interleukin (IL-17i) and IL-23i represent the cornerstone of the management of active disease. The use of these therapies obviously requires considering comorbidities presence, safety aspects and contraindications. AREAS COVERED The aim of this review is to describe the inflammatory mechanisms behind PsA comorbidities, and the role of bDMARDs in the prevention and treatment of these conditions in course of PsA. EXPERT OPINION Tailoring therapeutic strategies to the individual characteristics of each PsA patient can be an effective approach to manage comorbidities, maximizing the efficacy of bDMARDs, and reducing the incidence of AEs. Identifying targets within disease pathways can guide research into therapeutics that address both PsA and comorbidities simultaneously, but more studies are advocated for clarifying the potential prevention and management of bDMARDs used for PsA.
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Affiliation(s)
- Francesco Caso
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Mauro Fatica
- U.O.C. Reumatologia, Dipartimento di Medicina dei Sistemi, Universitá di Roma "Tor Vergata", Roma, Italy
| | - Mario Ferraioli
- U.O.C. Reumatologia, Dipartimento di Medicina dei Sistemi, Universitá di Roma "Tor Vergata", Roma, Italy
| | - Matteo Megna
- Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | - Luca Potestio
- Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | - Angelo Ruggiero
- Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | - Nello Tommasino
- Section of Dermatology - Department of Clinical Medicine and Surgery, University of Naples Federico II, Napoli, Italy
| | - Francesco Maione
- ImmunoPharmaLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Raffaele Scarpa
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Sole Chimenti
- U.O.C. Reumatologia, Dipartimento di Medicina dei Sistemi, Universitá di Roma "Tor Vergata", Roma, Italy
| | - Luisa Costa
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
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24
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Krüger P, Hartinger R, Djabali K. Navigating Lipodystrophy: Insights from Laminopathies and Beyond. Int J Mol Sci 2024; 25:8020. [PMID: 39125589 PMCID: PMC11311807 DOI: 10.3390/ijms25158020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/06/2024] [Accepted: 07/16/2024] [Indexed: 08/12/2024] Open
Abstract
Recent research into laminopathic lipodystrophies-rare genetic disorders caused by mutations in the LMNA gene-has greatly expanded our knowledge of their complex pathology and metabolic implications. These disorders, including Hutchinson-Gilford progeria syndrome (HGPS), Mandibuloacral Dysplasia (MAD), and Familial Partial Lipodystrophy (FPLD), serve as crucial models for studying accelerated aging and metabolic dysfunction, enhancing our understanding of the cellular and molecular mechanisms involved. Research on laminopathies has highlighted how LMNA mutations disrupt adipose tissue function and metabolic regulation, leading to altered fat distribution and metabolic pathway dysfunctions. Such insights improve our understanding of the pathophysiological interactions between genetic anomalies and metabolic processes. This review merges current knowledge on the phenotypic classifications of these diseases and their associated metabolic complications, such as insulin resistance, hypertriglyceridemia, hepatic steatosis, and metabolic syndrome, all of which elevate the risk of cardiovascular disease, stroke, and diabetes. Additionally, a range of published therapeutic strategies, including gene editing, antisense oligonucleotides, and novel pharmacological interventions aimed at addressing defective adipocyte differentiation and lipid metabolism, will be explored. These therapies target the core dysfunctional lamin A protein, aiming to mitigate symptoms and provide a foundation for addressing similar metabolic and genetic disorders.
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Affiliation(s)
| | | | - Karima Djabali
- Epigenetics of Aging, Department of Dermatology and Allergy, TUM School of Medicine, Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich (TUM), 85748 Garching, Germany; (P.K.); (R.H.)
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25
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Hutchinson AL, Liddle DM, Monk JM, Ma DWL, Robinson LE. n-3 and n-6 Polyunsaturated Fatty Acids Modulate Macrophage-Myocyte Inflammatory Crosstalk and Improve Myocyte Insulin Sensitivity. Nutrients 2024; 16:2086. [PMID: 38999834 PMCID: PMC11243049 DOI: 10.3390/nu16132086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/14/2024] Open
Abstract
In obesity, circulating saturated fatty acids (SFAs) and inflammatory cytokines interfere with skeletal muscle insulin signaling, leading to whole body insulin resistance. Further, obese skeletal muscle is characterized by macrophage infiltration and polarization to the inflammatory M1 phenotype, which is central to the development of local inflammation and insulin resistance. While skeletal muscle-infiltrated macrophage-myocyte crosstalk is exacerbated by SFA, the effects of other fatty acids, such as n-3 and n-6 polyunsaturated fatty acids (PUFAs), are less studied. Thus, the objective of this study was to determine the effects of long-chain n-3 and n-6 PUFAs on macrophage M1 polarization and subsequent effects on myocyte inflammation and metabolic function compared to SFA. Using an in vitro model recapitulating obese skeletal muscle cells, differentiated L6 myocytes were cultured for 24 h with RAW 264.7 macrophage-conditioned media (MCM), followed by insulin stimulation (100 nM, 20 min). MCM was generated by pre-treating macrophages for 24 h with 100 μM palmitic acid (16:0, PA-control), arachidonic acid (20:4n-6, AA), or docosahexaenoic acid (22:6n-3, DHA). Next, macrophage cultures were stimulated with a physiological dose (10 ng/mL) of lipopolysaccharide for an additional 12 h to mimic in vivo obese endotoxin levels. Compared to PA, both AA and DHA reduced mRNA expression and/or secreted protein levels of markers for M1 (TNFα, IL-6, iNOS; p < 0.05) and increased those for M2 (IL-10, TGF-β; p < 0.05) macrophage polarization. In turn, AA- and DHA-derived MCM reduced L6 myocyte-secreted cytokines (TNFα, IL-6; p < 0.05) and chemokines (MCP-1, MIP-1β; p < 0.05). Only AA-derived MCM increased L6-myocyte phosphorylation of Akt (p < 0.05), yet this was inconsistent with improved insulin signaling, as only DHA-derived MCM improved L6 myocyte glucose uptake (p < 0.05). In conclusion, dietary n-3 and n-6 PUFAs may be a useful strategy to modulate macrophage-myocyte inflammatory crosstalk and improve myocyte insulin sensitivity in obesity.
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Affiliation(s)
| | | | | | | | - Lindsay E. Robinson
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada (J.M.M.); (D.W.L.M.)
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26
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Warmbrunn MV, Bahrar H, de Clercq NC, Koopen AM, de Groot PF, Rutten J, Joosten LAB, Kootte RS, Bouter KEC, ter Horst KW, Hartstra AV, Serlie MJ, Soeters MR, van Raalte DH, Davids M, Levin E, Herrema H, Riksen NP, Netea MG, Groen AK, Nieuwdorp M. Novel Proteome Targets Marking Insulin Resistance in Metabolic Syndrome. Nutrients 2024; 16:1822. [PMID: 38931177 PMCID: PMC11206392 DOI: 10.3390/nu16121822] [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: 03/14/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
CONTEXT/OBJECTIVE In order to better understand which metabolic differences are related to insulin resistance in metabolic syndrome (MetSyn), we used hyperinsulinemic-euglycemic (HE) clamps in individuals with MetSyn and related peripheral insulin resistance to circulating biomarkers. DESIGN/METHODS In this cross-sectional study, HE-clamps were performed in treatment-naive men (n = 97) with MetSyn. Subjects were defined as insulin-resistant based on the rate of disappearance (Rd). Machine learning models and conventional statistics were used to identify biomarkers of insulin resistance. Findings were replicated in a cohort with n = 282 obese men and women with (n = 156) and without (n = 126) MetSyn. In addition to this, the relation between biomarkers and adipose tissue was assessed by nuclear magnetic resonance imaging. RESULTS Peripheral insulin resistance is marked by changes in proteins related to inflammatory processes such as IL-1 and TNF-receptor and superfamily members. These proteins can distinguish between insulin-resistant and insulin-sensitive individuals (AUC = 0.72 ± 0.10) with MetSyn. These proteins were also associated with IFG, liver fat (rho 0.36, p = 1.79 × 10-9) and visceral adipose tissue (rho = 0.35, p = 6.80 × 10-9). Interestingly, these proteins had the strongest association in the MetSyn subgroup compared to individuals without MetSyn. CONCLUSIONS MetSyn associated with insulin resistance is characterized by protein changes related to body fat content, insulin signaling and pro-inflammatory processes. These findings provide novel targets for intervention studies and should be the focus of future in vitro and in vivo studies.
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Affiliation(s)
- Moritz V. Warmbrunn
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
- Amsterdam UMC, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
- Amsterdam UMC, Cardiovascular Sciences, Amsterdam Cardiovascular Sciences, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Harsh Bahrar
- Department of Internal Medicine, Radboud University Medical Center, 6525 EP Nijmegen, The Netherlands; (H.B.)
| | - Nicolien C. de Clercq
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Annefleur M. Koopen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Pieter F. de Groot
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Joost Rutten
- Department of Internal Medicine, Radboud University Medical Center, 6525 EP Nijmegen, The Netherlands; (H.B.)
| | - Leo A. B. Joosten
- Department of Internal Medicine, Radboud University Medical Center, 6525 EP Nijmegen, The Netherlands; (H.B.)
| | - Ruud S. Kootte
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Kristien E. C. Bouter
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Kasper W. ter Horst
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Annick V. Hartstra
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Mireille J. Serlie
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Maarten R. Soeters
- Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Daniel H. van Raalte
- Diabetes Center, Department of Endocrniology and Metabolism, Amsterdam UMC, VU University Medical Centers, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
- Amsterdam Cardiovascular Sciences, VU University, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands
| | - Mark Davids
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Evgeni Levin
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Hilde Herrema
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Niels P. Riksen
- Department of Internal Medicine, Radboud University Medical Center, 6525 EP Nijmegen, The Netherlands; (H.B.)
| | - Mihai G. Netea
- Department of Internal Medicine, Radboud University Medical Center, 6525 EP Nijmegen, The Netherlands; (H.B.)
| | - Albert K. Groen
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
| | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (M.V.W.); (N.C.d.C.); (P.F.d.G.); (R.S.K.); (A.K.G.)
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Thorp EB, Karlstaedt A. Intersection of Immunology and Metabolism in Myocardial Disease. Circ Res 2024; 134:1824-1840. [PMID: 38843291 PMCID: PMC11569846 DOI: 10.1161/circresaha.124.323660] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 04/15/2024] [Indexed: 06/12/2024]
Abstract
Immunometabolism is an emerging field at the intersection of immunology and metabolism. Immune cell activation plays a critical role in the pathogenesis of cardiovascular diseases and is integral for regeneration during cardiac injury. We currently possess a limited understanding of the processes governing metabolic interactions between immune cells and cardiomyocytes. The impact of this intercellular crosstalk can manifest as alterations to the steady state flux of metabolites and impact cardiac contractile function. Although much of our knowledge is derived from acute inflammatory response, recent work emphasizes heterogeneity and flexibility in metabolism between cardiomyocytes and immune cells during pathological states, including ischemic, cardiometabolic, and cancer-associated disease. Metabolic adaptation is crucial because it influences immune cell activation, cytokine release, and potential therapeutic vulnerabilities. This review describes current concepts about immunometabolic regulation in the heart, focusing on intercellular crosstalk and intrinsic factors driving cellular regulation. We discuss experimental approaches to measure the cardio-immunologic crosstalk, which are necessary to uncover unknown mechanisms underlying the immune and cardiac interface. Deeper insight into these axes holds promise for therapeutic strategies that optimize cardioimmunology crosstalk for cardiac health.
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Affiliation(s)
- Edward B. Thorp
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Anja Karlstaedt
- Department of Cardiology, Smidt Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
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28
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Nhau PT, Gamede M, Sibiya N. COVID-19-Induced Diabetes Mellitus: Comprehensive Cellular and Molecular Mechanistic Insights. PATHOPHYSIOLOGY 2024; 31:197-209. [PMID: 38651404 PMCID: PMC11036300 DOI: 10.3390/pathophysiology31020016] [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: 02/12/2024] [Revised: 04/06/2024] [Accepted: 04/07/2024] [Indexed: 04/25/2024] Open
Abstract
Despite evidence demonstrating the risks of developing diabetes mellitus because of SARS-CoV-2, there is, however, insufficient scientific data available to elucidate the relationship between diabetes mellitus and COVID-19. Research indicates that SARS-CoV-2 infection is associated with persistent damage to organ systems due to the systemic inflammatory response. Since COVID-19 is known to induce these conditions, further investigation is necessary to fully understand its long-term effects on human health. Consequently, it is essential to consider the effect of the COVID-19 pandemic when predicting the prevalence of diabetes mellitus in the future, especially since the incidence of diabetes mellitus was already on the rise before the pandemic. Additional research is required to fully comprehend the impact of SARS-CoV-2 infection on glucose tolerance and insulin sensitivity. Therefore, this article delves deeper into the current literature and links the perceived relationship between SARS-CoV-2 and diabetes. In addition, the article highlights the necessity for further research to fully grasp the mechanisms that SARS-CoV-2 utilises to induce new-onset diabetes. Where understanding and consensus are reached, therapeutic interventions to prevent the onset of diabetes could be proposed. Lastly, we propose advocating for the regular screening of diabetes and pre-diabetes, particularly for the high-risk population with a history of COVID-19 infection.
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Affiliation(s)
- Praise Tatenda Nhau
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda 6139, South Africa;
| | - Mlindeli Gamede
- Human Physiology Department, University of Pretoria, Pretoria 0028, South Africa;
| | - Ntethelelo Sibiya
- Pharmacology Division, Faculty of Pharmacy, Rhodes University, Makhanda 6139, South Africa;
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29
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Siewe N, Friedman A. A mathematical model of obesity-induced type 2 diabetes and efficacy of anti-diabetic weight reducing drug. J Theor Biol 2024; 581:111756. [PMID: 38307451 DOI: 10.1016/j.jtbi.2024.111756] [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: 08/17/2023] [Revised: 11/04/2023] [Accepted: 01/26/2024] [Indexed: 02/04/2024]
Abstract
The dominant paradigm for modeling the obesity-induced T2DM (type 2 diabetes mellitus) today focuses on glucose and insulin regulatory systems, diabetes pathways, and diagnostic test evaluations. The problem with this approach is that it is not possible to explicitly account for the glucose transport mechanism from the blood to the liver, where the glucose is stored, and from the liver to the blood. This makes it inaccurate, if not incorrect, to properly model the concentration of glucose in the blood in comparison to actual glycated hemoglobin (A1C) test results. In this paper, we develop a mathematical model of glucose dynamics by a system of ODEs. The model includes the mechanism of glucose transport from the blood to the liver, and from the liver to the blood, and explains how obesity is likely to lead to T2DM. We use the model to evaluate the efficacy of an anti-T2DM drug that also reduces weight.
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Affiliation(s)
- Nourridine Siewe
- School of Mathematics and Statistics, College of Science, Rochester Institute of Technology, Rochester, NY, USA.
| | - Avner Friedman
- Department of Mathematics, The Ohio State University, Columbus, OH, USA
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30
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Naik N, Patel M, Sen R. Developmental Impacts of Epigenetics and Metabolism in COVID-19. J Dev Biol 2024; 12:9. [PMID: 38390960 PMCID: PMC10885083 DOI: 10.3390/jdb12010009] [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: 12/31/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Developmental biology is intricately regulated by epigenetics and metabolism but the mechanisms are not completely understood. The situation becomes even more complicated during diseases where all three phenomena are dysregulated. A salient example is COVID-19, where the death toll exceeded 6.96 million in 4 years, while the virus continues to mutate into different variants and infect people. Early evidence during the pandemic showed that the host's immune and inflammatory responses to COVID-19 (like the cytokine storm) impacted the host's metabolism, causing damage to the host's organs and overall physiology. The involvement of angiotensin-converting enzyme 2 (ACE2), the pivotal host receptor for the SARS-CoV-2 virus, was identified and linked to epigenetic abnormalities along with other contributing factors. Recently, studies have revealed stronger connections between epigenetics and metabolism in COVID-19 that impact development and accelerate aging. Patients manifest systemic toxicity, immune dysfunction and multi-organ failure. Single-cell multiomics and other state-of-the-art high-throughput studies are only just beginning to demonstrate the extent of dysregulation and damage. As epigenetics and metabolism directly impact development, there is a crucial need for research implementing cutting-edge technology, next-generation sequencing, bioinformatics analysis, the identification of biomarkers and clinical trials to help with prevention and therapeutic interventions against similar threats in the future.
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Affiliation(s)
- Noopur Naik
- Department of Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
| | - Mansi Patel
- Institute of Genomics and Integrative Biology, Delhi 110007, India
| | - Rwik Sen
- Active Motif, Inc., Carlsbad, CA 92008, USA
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31
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Zhao X, Zheng J, Wang J, Li B, Huang W. Inhibition of Hyperglycemia and Hyperlipidemia by Blocking Toll-like Receptor 4: Comparison of Wild-Type and Toll-like Receptor 4 Gene Knockout Mice on Obesity and Diabetes Modeling. BIOLOGY 2024; 13:63. [PMID: 38275739 PMCID: PMC10813444 DOI: 10.3390/biology13010063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 01/05/2024] [Accepted: 01/20/2024] [Indexed: 01/27/2024]
Abstract
Innate immune receptor TLR4 plays an important role in glycolipid metabolism. The objective of this study is to investigate the inhibitory effects of blocking TLR4 on hyperglycemia and hyperlipidemia by comparing WT and TLR4-/- mice in obesity and diabetes modeling. The knockout of the TLR4 gene could prevent weight gain induced by a high-fat diet (HFD)/high-sugar and high-fat diet (HSHFD), and the differences in the responses existed between the sexes. It extends the time required to reach the obesity criteria. However, when mice were injected with intraperitoneal streptozotocin (STZ) after being fed by HSHFD for two months, TLR4-/- mice exhibited less weight loss than WT. Blocking TLR4 alleviated the changes in body weight and blood glucose, consequently reducing the efficiency of diabetes modeling, especially for male mice. Additionally, male TLR4-/- obese mice exhibit lower total cholesterol (TC) and low-density lipoprotein (LDL) levels in serum and less formation of fat droplets in the liver compared to WT. On the other hand, the knockout of TLR4 significantly increased the high-density lipoprotein (HDL) of male mice. This study should provide new insights into the role of TLR4, as well as opportunities to target novel approaches to the prevention and treatment of metabolic diseases like obesity and diabetes.
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Affiliation(s)
- Xingyu Zhao
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China;
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China;
| | - Jiawei Zheng
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China;
| | - Jing Wang
- College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
| | - Bin Li
- College of Food Science, Shenyang Agricultural University, Shenyang 110866, China;
| | - Wuyang Huang
- Institute of Agro-Product Processing, Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China;
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang 212013, China;
- College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China;
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32
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Rabbani N, Thornalley PJ. Hexokinase-linked glycolytic overload and unscheduled glycolysis in hyperglycemia-induced pathogenesis of insulin resistance, beta-cell glucotoxicity, and diabetic vascular complications. Front Endocrinol (Lausanne) 2024; 14:1268308. [PMID: 38292764 PMCID: PMC10824962 DOI: 10.3389/fendo.2023.1268308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/12/2023] [Indexed: 02/01/2024] Open
Abstract
Hyperglycemia is a risk factor for the development of insulin resistance, beta-cell glucotoxicity, and vascular complications of diabetes. We propose the hypothesis, hexokinase-linked glycolytic overload and unscheduled glycolysis, in explanation. Hexokinases (HKs) catalyze the first step of glucose metabolism. Increased flux of glucose metabolism through glycolysis gated by HKs, when occurring without concomitant increased activity of glycolytic enzymes-unscheduled glycolysis-produces increased levels of glycolytic intermediates with overspill into effector pathways of cell dysfunction and pathogenesis. HK1 is saturated with glucose in euglycemia and, where it is the major HK, provides for basal glycolytic flux without glycolytic overload. HK2 has similar saturation characteristics, except that, in persistent hyperglycemia, it is stabilized to proteolysis by high intracellular glucose concentration, increasing HK activity and initiating glycolytic overload and unscheduled glycolysis. This drives the development of vascular complications of diabetes. Similar HK2-linked unscheduled glycolysis in skeletal muscle and adipose tissue in impaired fasting glucose drives the development of peripheral insulin resistance. Glucokinase (GCK or HK4)-linked glycolytic overload and unscheduled glycolysis occurs in persistent hyperglycemia in hepatocytes and beta-cells, contributing to hepatic insulin resistance and beta-cell glucotoxicity, leading to the development of type 2 diabetes. Downstream effector pathways of HK-linked unscheduled glycolysis are mitochondrial dysfunction and increased reactive oxygen species (ROS) formation; activation of hexosamine, protein kinase c, and dicarbonyl stress pathways; and increased Mlx/Mondo A signaling. Mitochondrial dysfunction and increased ROS was proposed as the initiator of metabolic dysfunction in hyperglycemia, but it is rather one of the multiple downstream effector pathways. Correction of HK2 dysregulation is proposed as a novel therapeutic target. Pharmacotherapy addressing it corrected insulin resistance in overweight and obese subjects in clinical trial. Overall, the damaging effects of hyperglycemia are a consequence of HK-gated increased flux of glucose metabolism without increased glycolytic enzyme activities to accommodate it.
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Affiliation(s)
| | - Paul J. Thornalley
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
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33
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Avtanski D, Stojchevski R. Significance of Adipose Tissue as an Endocrine Organ. CONTEMPORARY ENDOCRINOLOGY 2024:1-46. [DOI: 10.1007/978-3-031-72570-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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34
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Townsend LK, Steinberg GR. AMPK and the Endocrine Control of Metabolism. Endocr Rev 2023; 44:910-933. [PMID: 37115289 DOI: 10.1210/endrev/bnad012] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 03/10/2023] [Accepted: 04/24/2023] [Indexed: 04/29/2023]
Abstract
Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress-induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.
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Affiliation(s)
- Logan K Townsend
- Centre for Metabolism Obesity and Diabetes Research, Hamilton, ON L8S 4L8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Gregory R Steinberg
- Centre for Metabolism Obesity and Diabetes Research, Hamilton, ON L8S 4L8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, ON L8S 4L8, Canada
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada
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35
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Herremans KM, Underwood PW, Riner AN, Neal DW, Tushoski-Alemán GW, Forsmark CE, Nassour I, Han S, Hughes SJ. A protein-based machine learning approach to the identification of inflammatory subtypes in pancreatic ductal adenocarcinoma. Pancreatology 2023; 23:615-621. [PMID: 37391359 PMCID: PMC10528923 DOI: 10.1016/j.pan.2023.06.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 06/07/2023] [Accepted: 06/14/2023] [Indexed: 07/02/2023]
Abstract
BACKGROUND/OBJECTIVES The inherently immunosuppressive tumor microenvironment along with the heterogeneity of pancreatic ductal adenocarcinoma (PDAC) limits the effectiveness of available treatment options and contributes to the disease lethality. Using a machine learning algorithm, we hypothesized that PDAC may be categorized based on its microenvironment inflammatory milieu. METHODS Fifty-nine tumor samples from patients naïve to treatment were homogenized and probed for 41 unique inflammatory proteins using a multiplex assay. Subtype clustering was determined using t-distributed stochastic neighbor embedding (t-SNE) machine learning analysis of cytokine/chemokine levels. Statistics were performed using Wilcoxon rank sum test and Kaplan-Meier survival analysis. RESULTS t-SNE analysis of tumor cytokines/chemokines revealed two distinct clusters, immunomodulating and immunostimulating. In pancreatic head tumors, patients in the immunostimulating group (N = 26) were more likely to be diabetic (p = 0.027), but experienced less intraoperative blood loss (p = 0.0008). Though there were no significant differences in survival (p = 0.161), the immunostimulating group trended toward longer median survival by 9.205 months (11.28 vs. 20.48 months). CONCLUSION A machine learning algorithm identified two distinct subtypes within the PDAC inflammatory milieu, which may influence diabetes status as well as intraoperative blood loss. Opportunity exists to further explore how these inflammatory subtypes may influence treatment response, potentially elucidating targetable mechanisms of PDAC's immunosuppressive tumor microenvironment.
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Affiliation(s)
- Kelly M Herremans
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Patrick W Underwood
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Andrea N Riner
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Daniel W Neal
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | | | - Christopher E Forsmark
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Florida College of Medicine, Gainesville, FL, USA
| | - Ibrahim Nassour
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Song Han
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA
| | - Steven J Hughes
- Department of Surgery, University of Florida College of Medicine, Gainesville, FL, USA.
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36
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Gan L, Li N, Heizhati M, Li M, Yao L, Hong J, Wu T, Wang H, Liu M, Maitituersun A. Diurnal Cortisol Features and Type 2 Diabetes Risk in Patients With Hypertension and Obstructive Sleep Apnea: A Cohort Study. J Clin Endocrinol Metab 2023; 108:e679-e686. [PMID: 37022782 DOI: 10.1210/clinem/dgad184] [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: 10/05/2022] [Revised: 02/20/2023] [Accepted: 03/28/2023] [Indexed: 04/07/2023]
Abstract
CONTEXT The hypothalamic-pituitary-adrenal (HPA) axis may be associated with type 2 diabetes (T2D); however, whether HPA axis dysfunction is associated with incident T2D remains unclear in patients with hypertension and obstructive sleep apnea (OSA). OBJECTIVE To investigate the relationship between the diurnal cortisol features and the risk of incident T2D in patients with hypertension and OSA. METHODS Participants with cortisol rhythm test at baseline in the Urumqi Research on Sleep Apnea and Hypertension cohort were enrolled. The Cox regression model was used to evaluate the relationship between ln-transformed diurnal cortisol features and T2D risk. Stratified and sensitivity analyses were also performed. RESULTS A total of 1478 patients with hypertension and OSA were enrolled in this study. During a median follow-up of 7.0 years, 196 participants developed T2D. Overall, a steep diurnal cortisol slope (DCS) was significantly associated with decreased T2D risk (per SD increase, HR 0.88, 95% CI 0.79-0.97, P = .014). Midnight cortisol was positively associated with increased T2D risk (per SD increase, HR 1.25, 95% CI 1.08-1.45, P = .003). Sensitivity analyses showed similar results. Neither DCS nor midnight cortisol was associated with incident T2D in the women's subgroup or participants with mild OSA. CONCLUSION Steeper DCS and higher midnight cortisol levels are associated with lower and higher T2D risks in patients with hypertension and OSA, respectively, at least in men or participants with moderate to severe OSA. Diurnal cortisol features may represent an early prevention target for diabetes in this population.
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Affiliation(s)
- Lin Gan
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Nanfang Li
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Mulalibieke Heizhati
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Mei Li
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Ling Yao
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Jing Hong
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Ting Wu
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Hui Wang
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Miaomiao Liu
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
| | - Adalaiti Maitituersun
- Hypertension Center of People's Hospital of Xinjiang Uygur Autonomous Region, Xinjiang Hypertension Institute, NHC Key Laboratory of Hypertension Clinical Research, Key Laboratory of Xinjiang Uygur Autonomous Region "Hypertension Research Laboratory", Xinjiang Clinical Medical Research Center for Hypertension (Cardio-Cerebrovascular) Diseases, Urumqi, Xinjiang 830001, China
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Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol 2023; 20:475-494. [PMID: 36927772 DOI: 10.1038/s41569-023-00847-5] [Citation(s) in RCA: 170] [Impact Index Per Article: 85.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/08/2023] [Indexed: 03/18/2023]
Abstract
The prevalence of obesity has reached pandemic proportions, and now approximately 25% of adults in Westernized countries have obesity. Recognized as a major health concern, obesity is associated with multiple comorbidities, particularly cardiometabolic disorders. In this Review, we present obesity as an evolutionarily novel condition, summarize the epidemiological evidence on its detrimental cardiometabolic consequences and discuss the major mechanisms involved in the association between obesity and the risk of cardiometabolic diseases. We also examine the role of potential moderators of this association, with evidence for and against the so-called 'metabolically healthy obesity phenotype', the 'fatness but fitness' paradox or the 'obesity paradox'. Although maintenance of optimal cardiometabolic status should be a primary goal in individuals with obesity, losing body weight and, particularly, excess visceral adiposity seems to be necessary to minimize the risk of cardiometabolic diseases.
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Affiliation(s)
- Pedro L Valenzuela
- Physical Activity and Health Research Group (PaHerg), Research Institute of Hospital 12 de Octubre ("i + 12"), Madrid, Spain.
- Department of Systems Biology, University of Alcalá, Alcalá de Henares, Spain.
| | - Pedro Carrera-Bastos
- Center for Primary Health Care Research, Department of Clinical Sciences, Lund University, Malmö, Sweden
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain
| | | | - Daniel E Lieberman
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
| | - Alejandro Santos-Lozano
- Physical Activity and Health Research Group (PaHerg), Research Institute of Hospital 12 de Octubre ("i + 12"), Madrid, Spain
- Department of Health Sciences, European University Miguel de Cervantes, Valladolid, Spain
| | - Alejandro Lucia
- Faculty of Sport Sciences, Universidad Europea de Madrid, Madrid, Spain.
- CIBER of Frailty and Healthy Aging (CIBERFES), Madrid, Spain.
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Guttapadu R, Korla K, Uk S, Annam V, Ashok P, Chandra N. Identification of Probucol as a candidate for combination therapy with Metformin for Type 2 diabetes. NPJ Syst Biol Appl 2023; 9:18. [PMID: 37221264 DOI: 10.1038/s41540-023-00275-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 04/26/2023] [Indexed: 05/25/2023] Open
Abstract
Type 2 Diabetes (T2D) is often managed with metformin as the drug of choice. While it is effective overall, many patients progress to exhibit complications. Strategic drug combinations to tackle this problem would be useful. We constructed a genome-wide protein-protein interaction network capturing a global perspective of perturbations in diabetes by integrating T2D subjects' transcriptomic data. We computed a 'frequently perturbed subnetwork' in T2D that captures common perturbations across tissue types and mapped the possible effects of Metformin onto it. We then identified a set of remaining T2D perturbations and potential drug targets among them, related to oxidative stress and hypercholesterolemia. We then identified Probucol as the potential co-drug for adjunct therapy with Metformin and evaluated the efficacy of the combination in a rat model of diabetes. We find Metformin-Probucol at 5:0.5 mg/kg effective in restoring near-normal serum glucose, lipid, and cholesterol levels.
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Affiliation(s)
- Ranjitha Guttapadu
- IISc Mathematics Initiative, Indian Institute of Science, Bengaluru, Karnataka, 560012, India
| | - Kalyani Korla
- Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, 560012, India
| | - Safnaz Uk
- Department of Pharmacology, K.L.E. University's College of Pharmacy, Bangalore, Karnataka, 560010, India
| | - Vamseedhar Annam
- Department of Pathology, Rajarajeshwari Medical College and Hospital, Bangalore, Karnataka, 560074, India
| | - Purnima Ashok
- Department of Pharmacology, K.L.E. University's College of Pharmacy, Bangalore, Karnataka, 560010, India
| | - Nagasuma Chandra
- IISc Mathematics Initiative, Indian Institute of Science, Bengaluru, Karnataka, 560012, India.
- Department of Biochemistry, Indian Institute of Science, Bangalore, Karnataka, 560012, India.
- Centre for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru, Karnataka, 560012, India.
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Jalal MM, Mir R, Hamadi A, Altayar MA, Elfaki I, Barnawi J, Alkayyal AA, Amr M, Hadeel J, Moawadh MS, Alsaedi BSO, Alhelali MH, Yousif A. Association of Genetic and Allelic Variants of Von Willebrand Factor (VWF), Glutathione S-Transferase and Tumor Necrosis Factor Alpha with Ischemic Stroke Susceptibility and Progression in the Saudi Population. Life (Basel) 2023; 13:life13051200. [PMID: 37240845 DOI: 10.3390/life13051200] [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: 03/09/2023] [Revised: 04/25/2023] [Accepted: 05/11/2023] [Indexed: 05/28/2023] Open
Abstract
Stroke is a key cerebrovascular disease and important cause of death and disability worldwide, including in the kingdom of Saudi Arabia (KSA). It has a large economic burden and serious socioeconomic impacts on patients, their families and the community. The incidence of ischemic stroke is probably increased by the interaction of GSTT1 and GSTM1 null genotypes with high blood pressure, diabetes and cigarette smoking. The roles of VWF, GSTs and TNF-alpha gene variations in the induction of stroke are still uncertain and require further examination. In the current study, we studied the associations of SNPs in the genes VWF, GSTs and TNF-alpha with stroke in the Saudi population. Genotyping was performed using the ARMS -PCR for TNF-alpha, AS-PCR for VWF and multiplex PCR for GSTs. The study included 210 study subjects: 100 stroke cases and 110 healthy controls. We obtained significant distributions of VWF rs61748511 T > C, TNF-alpha rs1800629 G > A and GST rs4025935 and rs71748309 genotypes between stroke cases and the healthy controls (p < 0.05). The results also indicated that the TNF-alpha A allele was associated with risk of stroke with odd ratio (OR) = 2.22 and risk ratio = RR 2.47, p < 0.05. Similarly, the VWF-TC genotype and C allele were strongly linked with stroke with OR = 8.12 and RR 4.7, p < 0.05. In addition, GSTT1 and GSTT1 null genotype was strongly associated with stroke predisposition with OR = 8.30 and RR = 2.25, p < 0.0001. We conclude that there is a possible strong association between the VWF-T > C, TNF-alpha G > A, GSTT1 gene variants and ischemic stroke susceptibility in the Saudi population. However, future well-designed and large-scale case-control studies on protein-protein interactions and protein functional studies are required to verify these findings and examine the effects of these SNPs on these proteins.
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Affiliation(s)
- Mohammed M Jalal
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
- Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Rashid Mir
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
- Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Abdullah Hamadi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
- Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Malik A Altayar
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
- Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Imadeldin Elfaki
- Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Jameel Barnawi
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
- Prince Fahad Bin Sultan Chair for Biomedical Research, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Almohanad A Alkayyal
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Mouminah Amr
- Neuroscience Center, King Abdullah Medical Complex, Jeddah 23816, Saudi Arabia
| | - Jabali Hadeel
- Department of Radiology, King Abdullah Medical Complex, Jeddah 23816, Saudi Arabia
| | - Mamdoh S Moawadh
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Basim S O Alsaedi
- Department of Statistics, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Marwan H Alhelali
- Department of Statistics, University of Tabuk, Tabuk 71491, Saudi Arabia
| | - Aadil Yousif
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia
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Jønck S, Adamsen ML, Højgaard P, Rasmussen IE, Ellingsgaard H, Lund MAV, Jørgensen PG, Jacobsen S, Køber L, Vejlstrup N, Dreyer L, Pedersen BK, Berg RMG, Christensen RH. Effect of a 12-week high-intensity exercise intervention: a comparison of cardiac exercise adaptations during biological disease-modifying antirheumatic drug treatment (TNF inhibitors vs IL-6 signalling inhibitors) in patients with rheumatoid arthritis - study protocol for a randomised controlled trial. BMJ Open 2023; 13:e068600. [PMID: 37169504 PMCID: PMC10186416 DOI: 10.1136/bmjopen-2022-068600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 04/26/2023] [Indexed: 05/13/2023] Open
Abstract
INTRODUCTION The chronic inflammatory state in rheumatoid arthritis (RA) augments the risk of cardiovascular disease (CVD), with pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin 6 (IL-6) playing a vital role. Consequently, biological disease-modifying antirheumatic drugs (bDMARDs) may attenuate that risk. IL-6 is also a myokine, secreted from exercising skeletal muscles, where IL-6 exhibits anti-inflammatory effects that may ameliorate the risk of CVD. In healthy humans treated with IL-6 signalling inhibitors (IL-6i), exercise induced loss of visceral fat mass and cardiac adaptations were abolished. We hypothesise that IL-6 signalling inhibition will impair the cardiac and metabolic adaptions to exercise training compared with TNF inhibition in RA patients. METHODS AND ANALYSIS 80 RA patients treated with IL-6i (n=40) or TNF inhibitors (n=40) are included in a 12-week randomised investigator-blinded 4×4 min high-intensity interval training (HIIT) study. Patients are stratified for medical treatment and sex and allocated 1:1 to an exercise or a no exercise control group (four groups). The supervised exercise intervention comprises 3 weekly HIIT sessions on an ergometer bicycle. The primary outcome is the change in left ventricular mass (LVM), and key secondary outcome is change in visceral fat mass. Both outcomes are measured by MRI. Primary statistical analysis will evaluate LVM at follow-up in a regression model. Intention-to-treat and per protocol analyses will be conducted. The latter necessitates a minimum attendance rate of 80%, adherence to bDMARDs treatment of ≥80% and minimum 8 min (50%) of maximal heart rate above 85% per session. ETHICS AND DISSEMINATION The study has been approved by the Capital Region Ethics Committee (H-21010559 amendments 86424, 87463 and 88044) and the Danish Medicines Agency (2021-b005287-21). The trial will follow ICH-GCP guidelines. Regardless of outcome, results will be published in relevant peer-reviewed journals. TRIAL REGISTRATION NUMBERS Eudra-CT: 2021-b005287-21 and NCT05215509.
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Affiliation(s)
- Simon Jønck
- Centre for Physical Activity Research, Copenhagen University Hospital, Copenhagen, Denmark
| | - Malte Lund Adamsen
- Centre for Physical Activity Research, Copenhagen University Hospital, Copenhagen, Denmark
- Copenhagen Research Center for Autoimmune Connective Tissue Diseases, COPEACT, Rigshospitalet, Copenhagen, Denmark
| | - Pil Højgaard
- Department of Internal Medicine M2, Rheumatology, Holbaek Sygehus, Holbaek, Denmark
| | | | - Helga Ellingsgaard
- Centre for Physical Activity Research, Copenhagen University Hospital, Copenhagen, Denmark
| | - Morten Asp Vonsild Lund
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
- Deparment of Biomedical Sciences, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
| | | | - Søren Jacobsen
- Copenhagen Research Center for Autoimmune Connective Tissue Diseases, COPEACT, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Medicine, Rigshospitalet, Copenhagen, Denmark
| | - Lars Køber
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Niels Vejlstrup
- Department of Cardiology, Rigshospitalet, Copenhagen, Denmark
| | - Lene Dreyer
- Center of Rheumatic Research Aalborg (CERRA), Department of Rheumatology, Aalborg Universitetshospital, Aalborg, Denmark
| | | | - Ronan M G Berg
- Deparment of Biomedical Sciences, University of Copenhagen Faculty of Health and Medical Sciences, Copenhagen, Denmark
- Department of Clinical Physiology and Nuclear Medicine, Rigshospitalet, Copenhagen, Denmark
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Su Z, Li H, Ye Z, Zhu Y, Feng B, Tang L, Zheng G. Qidan Tiaozhi capsule attenuates metabolic syndrome via activating AMPK/PINK1-Parkin-mediated mitophagy. JOURNAL OF ETHNOPHARMACOLOGY 2023; 307:116091. [PMID: 36592823 DOI: 10.1016/j.jep.2022.116091] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 12/10/2022] [Accepted: 12/21/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Qidan Tiaozhi capsule (QD), a traditional Chinese medicine, has been used to treat metabolic syndrome for over a decade. However, the mechanism of QD in the treatment of metabolic syndrome is still unknown. AIM OF THE STUDY Growing studies demonstrate that impaired mitophagy is one of the important causes of metabolic syndrome. Thus, this research aims to investigate the mechanism of mitophagy in the QD treatment of metabolic syndrome. MATERIALS AND METHODS Network pharmacology and molecular docking were used to probe the mechanism of QD treatment of metabolic syndrome. In an oleic acid-induced cell model, glucose consumption and uptake capacity, triglyceride (TG), total cholesterol (TC), malonaldehyde (MDA), superoxide dismutase (SOD) and ROS levels, and mitochondrial membrane potential (MMP) were examined. mRFP-GFP-LC3 adenovirus and GFP-LC3 lentivirus were used to examine the effect of QD on mitophagy. The IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were also determined. What's more, the PINK1 gene was silenced to verify the above findings. In a high-fat diet-fed mouse model, body weight, organ indexes, OGTT, ITT, HOMA-IR, insulin sensitivity, serum MDA, SOD, TC, TG, LDL-C and HDL-C, hepatic TC, TG, LDL-C and HDL-C levels, hepatic steatosis, and IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were investigated. RESULTS Results from network pharmacology and molecular docking suggested that QD might suppress oxidative stress to improve metabolic syndrome. In an oleic acid-induced cell model, compared with the model group, enhanced glucose consumption and uptake ability, inhibited intracellular lipid accumulation, TC, TG, MDA and ROS levels, and increased SOD level and MMP were found in QD groups. And mitophagy levels, IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were promoted. Interestingly, PINK1 silencing reversed the therapeutic action of QD on oleic acid-induced cells. In high-fat diet-fed mice, inhibited body weight, abdominal fat indexes, liver indexes, HOMA-IR, serum and hepatic TC, TG and LDL-C, serum MDA and hepatic steatosis, and increased insulin sensitivity, serum and hepatic HDL-C, serum SOD, and activated IRS2-PI3K and AMPK/PINK1-Parkin signal pathways were found in QD groups. CONCLUSION QD activates AMPK/PINK1-Parkin-mediated mitophagy to suppress oxidative stress to treat metabolic syndrome.
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Affiliation(s)
- Zuqing Su
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hongxia Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zeting Ye
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Zhu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bing Feng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Lipeng Tang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangjuan Zheng
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Department of Pharmacology of Traditional Chinese Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
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Legaard GE, Lyngbæk MPP, Almdal TP, Karstoft K, Bennetsen SL, Feineis CS, Nielsen NS, Durrer CG, Liebetrau B, Nystrup U, Østergaard M, Thomsen K, Trinh B, Solomon TPJ, Van Hall G, Brønd JC, Holst JJ, Hartmann B, Christensen R, Pedersen BK, Ried-Larsen M. Effects of different doses of exercise and diet-induced weight loss on beta-cell function in type 2 diabetes (DOSE-EX): a randomized clinical trial. Nat Metab 2023; 5:880-895. [PMID: 37127822 PMCID: PMC10229430 DOI: 10.1038/s42255-023-00799-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 04/04/2023] [Indexed: 05/03/2023]
Abstract
Diet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).
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Affiliation(s)
- Grit E Legaard
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Mark P P Lyngbæk
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Thomas P Almdal
- Department of Endocrinology PE, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Department of Immunology & Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Kristian Karstoft
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
- Department of Clinical Pharmacology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | | | - Camilla S Feineis
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Nina S Nielsen
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Cody G Durrer
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | | | - Ulrikke Nystrup
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Martin Østergaard
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Katja Thomsen
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Beckey Trinh
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | | | - Gerrit Van Hall
- Biomedical Sciences, Faculty of Health & Medical Science, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Clinical Biochemistry, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark
| | - Jan Christian Brønd
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Robin Christensen
- Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
- Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Bente K Pedersen
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark
| | - Mathias Ried-Larsen
- Centre for Physical Activity Research, Rigshospitalet, Copenhagen, Denmark.
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark.
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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Sergi D, Sanz JM, Lazzer S, Brombo G, Zuliani G, Biolo G, Šimunič B, Pišot R, Dalla Nora E, Passaro A. Interleukin-18 Is a Potential Biomarker Linking Dietary Fatty Acid Quality and Insulin Resistance: Results from a Cross-Sectional Study in Northern Italy. Nutrients 2023; 15:nu15071782. [PMID: 37049621 PMCID: PMC10097292 DOI: 10.3390/nu15071782] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/08/2023] Open
Abstract
Dietary lipids are pivotal in modulating metabolic inflammation. Among the inflammatory mediators characterizing metabolic inflammation, interleukin 18 (IL-18) has been consistently associated with obesity and insulin resistance. This study aims to evaluate whether the quality of lipid intake impacts upon IL-18 plasma levels and the implications on insulin resistance computed by the homeostatic model assessment for insulin resistance (HOMA-IR). Using a cross-sectional design, this study confirmed that IL-18 correlated positively with insulin resistance and individuals with a HOMA-IR ≥ 2.5 displayed higher circulating IL-18 levels compared with their insulin-sensitive counterparts. In terms of the effect of the quality of dietary lipids on IL-18 circulating levels, the ratio between monounsaturated, omega-3, polyunsaturated and saturated fatty acids as well as the intake of eicosapentaenoic and docosahexaenoic acids correlated negatively with IL-18. Despite this, IL-18 circulating levels, but not dietary fatty acid quality, predicted insulin resistance. Nevertheless, the ratio between omega 3 and saturated fatty acids was a predictor of IL-18 plasma levels. Thus, the downregulation of IL-18 may underpin, at least partially, the beneficial metabolic effects of substituting omega 3 for saturated fatty acids with this cytokine potentially representing a biomarker linking dietary lipids and metabolic outcomes.
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Affiliation(s)
- Domenico Sergi
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, 46, I-44121 Ferrara, Italy
| | - Juana Maria Sanz
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Via Luigi Borsari, 46, I-44121 Ferrara, Italy
| | - Stefano Lazzer
- Department of Medicine, University of Udine, Piazzale M. Kolbe 4, I-33100 Udine, Italy
| | - Gloria Brombo
- Medical Department, University Hospital of Ferrara Arcispedale Sant’Anna, Via A. Moro 8, I-44124 Ferrara, Italy
| | - Giovanni Zuliani
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, 46, I-44121 Ferrara, Italy
- Medical Department, University Hospital of Ferrara Arcispedale Sant’Anna, Via A. Moro 8, I-44124 Ferrara, Italy
| | - Gianni Biolo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, Strada di Fiume, 447, I-34149 Trieste, Italy
| | - Boštjan Šimunič
- Institute for Kinesiology Research, Science and Research Centre of Koper, Garibaldijeva 1, SI-6000 Koper, Slovenia
| | - Rado Pišot
- Institute for Kinesiology Research, Science and Research Centre of Koper, Garibaldijeva 1, SI-6000 Koper, Slovenia
| | - Edoardo Dalla Nora
- Medical Department, University Hospital of Ferrara Arcispedale Sant’Anna, Via A. Moro 8, I-44124 Ferrara, Italy
| | - Angelina Passaro
- Department of Translational Medicine, University of Ferrara, Via Luigi Borsari, 46, I-44121 Ferrara, Italy
- Medical Department, University Hospital of Ferrara Arcispedale Sant’Anna, Via A. Moro 8, I-44124 Ferrara, Italy
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Loss of brain energy metabolism control as a driver for memory impairment upon insulin resistance. Biochem Soc Trans 2023; 51:287-301. [PMID: 36606696 DOI: 10.1042/bst20220789] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/10/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023]
Abstract
The pathophysiological mechanisms intersecting metabolic and neurodegenerative disorders include insulin resistance, which has a strong involvement of environmental factors. Besides central regulation of whole-body homeostasis, insulin in the central nervous system controls molecular signalling that is critical for cognitive performance, namely signalling through pathways that modulate synaptic transmission and plasticity, and metabolism in neurons and astrocytes. This review provides an overview on how insulin signalling in the brain might regulate brain energy metabolism, and further identified molecular mechanisms by which brain insulin resistance might impair synaptic fuelling, and lead to cognitive deterioration.
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Gether L, Storgaard H, Kezic S, Jakasa I, Hartmann B, Skov-Jeppesen K, Holst JJ, Pedersen AJ, Forman J, van Hall G, Sørensen OE, Skov L, Røpke MA, Knop FK, Thyssen JP. Effects of topical corticosteroid versus tacrolimus on insulin sensitivity and bone homeostasis in adults with atopic dermatitis-A randomized controlled study. Allergy 2023. [PMID: 36824052 DOI: 10.1111/all.15690] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 01/06/2023] [Accepted: 01/24/2023] [Indexed: 02/25/2023]
Abstract
INTRODUCTION Topical corticosteroids (TCS), used to treat atopic dermatitis (AD), have been associated with type 2 diabetes and osteoporosis in epidemiological studies, possibly explained by systemic absorption. OBJECTIVES We examined whether intensive daily whole-body TCS treatment over 2 weeks followed by twice weekly application for 4 weeks could elicit insulin resistance and increase bone resorption in adults with AD. METHODS A randomized parallel-group double-blind double-dummy non-corticosteroid-based active comparator study design was completed in Copenhagen, Denmark. Thirty-six non-obese, non-diabetic adults with moderate-to-severe AD were randomized to whole-body treatment with betamethasone 17-valerate 0.1% plus a vehicle once daily or tacrolimus 0.1% twice daily after washout. Insulin sensitivity assessed by the hyperinsulinemic-euglycemic clamp combined with tracer infusions and biomarkers of bone formation (P1NP) and resorption (CTX) were evaluated at baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment. RESULTS AD severity improved with both treatments and systemic inflammation was reduced. After 2 weeks, we observed similar increase in peripheral insulin sensitivity with use of betamethasone (n = 18) and tacrolimus (n = 18). Bone resorption biomarker, CTX, was unchanged, while bone formation marker, P1NP, decreased after betamethasone treatment after both 2 and 6 weeks but remained unchanged in the tacrolimus arm. CONCLUSIONS Whole-body treatment with TCS leads to systemic exposure but appears not to compromise glucose metabolism during short-term use, which may be a result of reduced systemic inflammatory activity. The negative impact on bone formation could be regarded an adverse effect of TCS.
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Affiliation(s)
- Lise Gether
- Center for Clinical Metabolic Research, Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Dermatology and Allergy, Copenhagen Research Group for Inflammatory Skin (CORGIS), Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- LEO Pharma A/S, Ballerup, Denmark
| | - Heidi Storgaard
- Center for Clinical Metabolic Research, Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Sanja Kezic
- Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Ivone Jakasa
- Department of Chemistry and Biochemistry, Laboratory for Analytical Chemistry, Faculty of Food Technology and Biotechnology, University of Zagreb, Zagreb, Croatia
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kirsa Skov-Jeppesen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Julie Forman
- Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Gerrit van Hall
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Metabolomics Core Facility, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Lone Skov
- Department of Dermatology and Allergy, Copenhagen Research Group for Inflammatory Skin (CORGIS), Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Mads A Røpke
- LEO Pharma A/S, Ballerup, Denmark
- Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jacob Pontoppidan Thyssen
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Dermatology and Venereology, Bispebjerg-Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
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Emerging Mechanisms of Skeletal Muscle Homeostasis and Cachexia: The SUMO Perspective. Cells 2023; 12:cells12040644. [PMID: 36831310 PMCID: PMC9953977 DOI: 10.3390/cells12040644] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 02/10/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
Mobility is an intrinsic feature of the animal kingdom that stimulates evolutionary processes and determines the biological success of animals. Skeletal muscle is the primary driver of voluntary movements. Besides, skeletal muscles have an immense impact on regulating glucose, amino acid, and lipid homeostasis. Muscle atrophy/wasting conditions are accompanied by a drastic effect on muscle function and disrupt steady-state muscle physiology. Cachexia is a complex multifactorial muscle wasting syndrome characterized by extreme loss of skeletal muscle mass, resulting in a dramatic decrease in life quality and reported mortality in more than 30% of patients with advanced cancers. The lack of directed treatments to prevent or relieve muscle loss indicates our inadequate knowledge of molecular mechanisms involved in muscle cell organization and the molecular etiology of cancer-induced cachexia (CIC). This review highlights the latest knowledge of regulatory mechanisms involved in maintaining muscle function and their deregulation in wasting syndromes, particularly in cachexia. Recently, protein posttranslational modification by the small ubiquitin-like modifier (SUMO) has emerged as a key regulatory mechanism of protein function with implications for different aspects of cell physiology and diseases. We also review an atypical association of SUMO-mediated pathways in this context and deliberate on potential treatment strategies to alleviate muscle atrophy.
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Yudaeva AD, Stafeev IS, Michurina SS, Menshikov MY, Shestakova MV, Parfyonova YV. The interactions between inflammation and insulin resistance: molecular mechanisms in insulin-producing and insulin-dependent tissues. DIABETES MELLITUS 2023. [DOI: 10.14341/dm12981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
In the modern world the prevalence of obesity and type 2 diabetes mellitus (T2DM) significantly increases. In this light the risks of obesity-associated complications also grow up. The crucial linkage between obesity and its metabolic and cardiovascular complications is inflammatory process. The mechanism of this linkage is similar in pancreas and insulin-dependent tissues both on cells, cell-to-cell communication and signaling pathway levels: the catalysts are different lipids (cholesterol, free fatty acids, triglycerides), which are able to activate Toll-like receptors of innate immunity and inflammation. Nextly, IKK- and JNK-dependent cascades activate the secretion of inflammatory cytokines TNFa, IL-1b, IL-6 and others, which act by paracrine and autocrine manner and support inflammation both in local and systemic levels. Thus, insulin-producing and insulin-dependent tissues, which are involved in T2DM pathogenesis, through the inflammatory process integrate in pathogenic and self-maintaining cycle, which leads to the suppression of insulin secretion, pancreatic β-cell failure and the development of insulin-dependent tissues insulin resistance.
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Affiliation(s)
- A. D. Yudaeva
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Pirogov Russian National Research Medical University
| | - I. S. Stafeev
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Pirogov Russian National Research Medical University
| | - S. S. Michurina
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Lomonosov Moscow State University
| | - M. Yu. Menshikov
- National Medical Research Centre of Cardiology named after academician E.I.Chazov
| | | | - Y. V. Parfyonova
- National Medical Research Centre of Cardiology named after academician E.I.Chazov; Lomonosov Moscow State University
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Lee H, Kim SY, Lim Y. Lespedeza bicolor extract supplementation reduced hyperglycemia-induced skeletal muscle damage by regulation of AMPK/SIRT/PGC1α-related energy metabolism in type 2 diabetic mice. Nutr Res 2023; 110:1-13. [PMID: 36638746 DOI: 10.1016/j.nutres.2022.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 12/19/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Lespedeza bicolor (LB) is known to have antidiabetic activities; however, the underlying molecular mechanisms of LB in hyperglycemia-induced skeletal muscle damage is unclear. Inflammation and oxidative stress caused by type 2 diabetes mellitus (T2DM) not only contributes to insulin resistance, but also promotes muscle atrophy via decreased muscle protein synthesis and increased protein degradation, leading to frailty and sarcopenia. In this study, we hypothesized that LB extract (LBE) supplementatin has an ameliorative effect on hyperglycemia-induced skeletal muscle damage by activation of 5' adenosine monophosphate-activated protein kinase (AMPK)/sirtuin (SIRT)/proliferator-activated receptor γ coactivator 1α (PGC1α)-associated energy metabolism in mice with T2DM. Diabetes was induced by a high-fat diet with a 2-time streptozotoxin injection (30 mg/kg body weight) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose level ≥140 mg/dL), the mice were administered with LBE at a low dose (100 mg/kg/d) or high dose (250 mg/kg/d) by gavage for 12 weeks. LBE supplementation ameliorated glucose tolerance and hemoglobin A1c (%) in mice with T2DM. Moreover, LBE supplementation upregulated protein levels of insulin receptor subunit-1 and Akt accompanied by increased translocation of glucose transporter 4 in mice with T2DM. Furthermore, LBE increased mitochondrial biogenesis by activating SIRT1, SIRT3, SIRT4, and peroxisome PGC1α in diabetic skeletal muscle. Meanwhile, LBE supplementation reduced oxidative stress and inflammation in mice with T2DM. Taken together, the current study suggested that LBE could be a potential therapeutic to prevent skeletal muscle damage by regulation AMPK/SIRT/PGC1α-related energy metabolism in T2DM.
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Affiliation(s)
- Heaji Lee
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Sun Yeou Kim
- College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
| | - Yunsook Lim
- Department of Food and Nutrition, Kyung Hee University, Seoul 02447, Republic of Korea.
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50
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Bensussen A, Torres-Magallanes JA, Roces de Álvarez-Buylla E. Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue. Front Immunol 2023; 14:1014778. [PMID: 37026009 PMCID: PMC10070947 DOI: 10.3389/fimmu.2023.1014778] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 02/27/2023] [Indexed: 04/08/2023] Open
Abstract
Background Visceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes. Methods We collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus. Results Stochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone. Conclusion Insulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.
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Affiliation(s)
- Antonio Bensussen
- *Correspondence: Antonio Bensussen, ; Elena Roces de Álvarez-Buylla,
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