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Mukherjee R, Pancholi P, Sharma M, Solomon H, Timaul MN, Thant C, McGriskin R, Hayatt O, Markov V, D'Allara J, Bekker S, Candelier J, Carrasco SE, de Stanchina E, Vanaja K, Rosen N. Diet induced insulin resistance is due to induction of PTEN expression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.25.645201. [PMID: 40196497 PMCID: PMC11974787 DOI: 10.1101/2025.03.25.645201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Insulin resistance is a condition associated with obesity, type 2 diabetes(T2D), hyperinsulinemia, hyperglycemia and defined by reduced sensitivity to insulin signaling. Molecular causes and early signaling events underlying insulin resistance are not well understood. Here we show that insulin activation of PI3K/AKT/mTOR signaling in insulin target tissues, causes mTORC1 induction of PTEN translation, a negative regulator of PI3K signaling. We hypothesized that insulin resistance is due to insulin dependent induction of PTEN that prevents further increases in PI3K signaling. In a diet induced animal model of obesity and insulin resistance, we show that PTEN levels are increased in fat, muscle, and liver. Hyperinsulinemia and PTEN induction are followed by hyperglycemia, severe glucose intolerance, and hepatic steatosis. In response to chronic hyperinsulinemia, PTEN remains increased, while AKT activity is induced transiently before settling down to a PTEN-high and AKT-low state in the tissues, predicted by computational modeling of the PTEN-AKT feedback loop. Treatment with PTEN and mTORC1 inhibitors prevent and reverse the effect of PTEN induction, rescue insulin resistance and increase PI3K/AKT signaling. Thus, we show that PTEN induction by increased insulin levels elevates feedback inhibition of the pathway causing insulin resistance, its associated phenotypes, and is a potential therapeutic target.
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2
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Den Hartogh DJ, MacPherson REK, Tsiani E. Muscle cell palmitate-induced insulin resistance, JNK, IKK/NF-κB, and STAT3 activation are attenuated by carnosic and rosmarinic acid. Appl Physiol Nutr Metab 2025; 50:1-14. [PMID: 39805098 DOI: 10.1139/apnm-2024-0302] [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] [Indexed: 01/16/2025]
Abstract
The worldwide epidemic of obesity has drastically worsened with the increase in more sedentary lifestyles and increased consumption of fatty foods. Increased blood free fatty acids, often observed in obesity, lead to impaired insulin action, and promote the development of insulin resistance and type 2 diabetes mellitus. c-Jun N-terminal kinase (JNK), inhibitor of kappa B (IκB) kinase (IKK)-nuclear factor-kappa B (NF-κB), and signal transducer and activator of transcription 3 (STAT3) are known to be involved in skeletal muscle insulin resistance. We reported previously that carnosic acid (CA) and rosmarinic acid (RA) attenuated the palmitate-induced skeletal muscle insulin resistance, an effect that was associated with increased AMPK activation and reduced mammalian target of rapamycin-p70S6K signaling. In the present study, we examined the effects of CA and RA on JNK, IKK-NF-κB, and STAT3. Exposure of cells to palmitate increased the phosphorylation/activation of JNK, IKKα/β, IκBα, NF-κBp65, and STAT3. Importantly, CA and RA attenuated the deleterious effects of palmitate. Our data indicate that CA and RA have the potential to counteract the palmitate-induced skeletal muscle cell insulin resistance by modulating JNK, IKK-NF-κB, and STAT3 signaling.
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Affiliation(s)
- Danja J Den Hartogh
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Neuroscience, Brock University, St. Catharines, ON L2S3A1, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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Wohlfert AJ, Phares J, Granholm AC. The mTOR Pathway: A Common Link Between Alzheimer's Disease and Down Syndrome. J Clin Med 2024; 13:6183. [PMID: 39458132 PMCID: PMC11508835 DOI: 10.3390/jcm13206183] [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: 09/04/2024] [Revised: 10/12/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Down syndrome (DS) is a chromosomal condition that causes many systemic dysregulations, leading to several possible age-related diseases including Alzheimer's disease (AD). This may be due to the triplication of the Amyloid precursor protein (APP) gene or other alterations in mechanistic pathways, such as the mTOR pathway. Impairments to upstream regulators of mTOR, such as insulin, PI3K/AKT, AMPK, and amino acid signaling, have been linked to amyloid beta plaques (Aβ) and neurofibrillary tangles (NFT), the most common AD pathologies. However, the mechanisms involved in the progression of pathology in human DS-related AD (DS-AD) are not fully investigated to date. Recent advancements in omics platforms are uncovering new insights into neurodegeneration. Genomics, spatial transcriptomics, proteomics, and metabolomics are novel methodologies that provide more data in greater detail than ever before; however, these methods have not been used to analyze the mTOR pathways in connection to DS-AD. Using these new techniques can unveil unexpected insights into pathological cellular mechanisms through an unbiased approach.
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Affiliation(s)
- Abigail J. Wohlfert
- Department of Modern Human Anatomy and Cell & Developmental Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;
| | - Jeremiah Phares
- Department of Neurosurgery, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA;
| | - Ann-Charlotte Granholm
- Department of Neurosurgery, University of Colorado Anschutz Medical Center, Aurora, CO 80045, USA;
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Liu T, Zhang J, Chang F, Sun M, He J, Ai D. Role of endothelial Raptor in abnormal arteriogenesis after lower limb ischaemia in type 2 diabetes. Cardiovasc Res 2024; 120:1218-1234. [PMID: 38722901 DOI: 10.1093/cvr/cvae105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 03/08/2024] [Accepted: 03/17/2024] [Indexed: 09/03/2024] Open
Abstract
AIMS Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM. METHODS AND RESULTS Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice. CONCLUSION Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM.
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Affiliation(s)
- Ting Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Jiachen Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Fangyuan Chang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Mengyu Sun
- Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Jinlong He
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Institute of Cardiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
- Department of Physiology and Pathophysiology, Tianjin Medical University, Qixiangtai Rd 22nd, Tianjin 300070, China
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Rosen N, Mukherjee R, Pancholi P, Sharma M, Solomon H, Timaul M, Thant C, McGriskin R, Hayatt O, Markov V, D'Allara J, Bekker S, Candelier J, Carrasco S, de Stanchina E, Vanaja K. Diet induced insulin resistance is due to induction of PTEN expression. RESEARCH SQUARE 2024:rs.3.rs-4021885. [PMID: 38978604 PMCID: PMC11230483 DOI: 10.21203/rs.3.rs-4021885/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
Type 2 Diabetes (T2D) is a condition that is often associated with obesity and defined by reduced sensitivity of PI3K signaling to insulin (insulin resistance), hyperinsulinemia and hyperglycemia. Molecular causes and early signaling events underlying insulin resistance are not well understood. Insulin activation of PI3K signaling causes mTOR dependent induction of PTEN translation, a negative regulator of PI3K signaling. We speculated that insulin resistance is due to insulin dependent induction of PTEN protein that prevent further increases in PI3K signaling. Here we show that in a diet induced model of obesity and insulin resistance, PTEN levels are increased in fat, muscle and liver tissues. Onset of hyperinsulinemia and PTEN induction in tissue is followed by hyperglycemia, hepatic steatosis and severe glucose intolerance. Treatment with a PTEN phosphatase inhibitor prevents and reverses these phenotypes, whereas an mTORC1 kinase inhibitor reverses all but the hepatic steatosis. These data suggest that induction of PTEN by increasing levels of insulin elevates feedback inhibition of the pathway to a point where downstream PI3K signaling is reduced and hyperglycemia ensues. PTEN induction is thus necessary for insulin resistance and the type 2 diabetes phenotype and a potential therapeutic target.
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Den Hartogh DJ, Vlavcheski F, Tsiani E. Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved. Int J Mol Sci 2023; 24:ijms24065094. [PMID: 36982168 PMCID: PMC10049470 DOI: 10.3390/ijms24065094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/16/2023] [Accepted: 01/26/2023] [Indexed: 03/30/2023] Open
Abstract
Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties.
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Affiliation(s)
- Danja J Den Hartogh
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Filip Vlavcheski
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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Jurca CM, Kozma K, Petchesi CD, Zaha DC, Magyar I, Munteanu M, Faur L, Jurca A, Bembea D, Severin E, Jurca AD. Tuberous Sclerosis, Type II Diabetes Mellitus and the PI3K/AKT/mTOR Signaling Pathways-Case Report and Literature Review. Genes (Basel) 2023; 14:433. [PMID: 36833359 PMCID: PMC9957184 DOI: 10.3390/genes14020433] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/23/2023] [Accepted: 02/05/2023] [Indexed: 02/11/2023] Open
Abstract
Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous syndrome. It is manifested mainly in cutaneous lesions, epilepsy and the emergence of hamartomas in several tissues and organs. The disease sets in due to mutations in two tumor suppressor genes: TSC1 and TSC2. The authors present the case of a 33-year-old female patient registered with the Bihor County Regional Center of Medical Genetics (RCMG) since 2021 with a TSC diagnosis. She was diagnosed with epilepsy at eight months old. At 18 years old she was diagnosed with tuberous sclerosis and was referred to the neurology department. Since 2013 she has been registered with the department for diabetes and nutritional diseases with a type 2 diabetes mellitus (T2DM) diagnosis. The clinical examination revealed: growth delay, obesity, facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs, frequent convulsive seizures; on a biological level, high glycemia and glycated hemoglobin levels. Brain MRI displayed a distinctive TS aspect with five bilateral hamartomatous subependymal nodules associating cortical/subcortical tubers with the frontal, temporal and occipital distribution. Molecular diagnosis showed a pathogenic variant in the TSC1 gene, exon 13, c.1270A>T (p. Arg424*). Current treatment targets diabetes (Metformin, Gliclazide and the GLP-1 analog semaglutide) and epilepsy (Carbamazepine and Clonazepam). This case report presents a rare association between type 2 diabetes mellitus and Tuberous Sclerosis Complex. We suggest that the diabetes medication Metformin may have positive effects on both the progression of the tumor associated with TSC and the seizures specific to TSC and we assume that the association of TSC and T2DM in the presented cases is accidental, as there are no similar cases reported in the literature.
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Affiliation(s)
- Claudia Maria Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Kinga Kozma
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Codruta Diana Petchesi
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
- Regional Center of Medical Genetics Bihor, County Emergency Clinical Hospital Oradea (Part of ERN-ITHACA), 410469 Oradea, Romania
| | - Dana Carmen Zaha
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Ioan Magyar
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Mihai Munteanu
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Lucian Faur
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Aurora Jurca
- Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
| | - Dan Bembea
- Faculty of Medicine, University of Medicine and Pharmacy ”Iuliu Hațieganu”, 400012 Cluj Napoca, Romania
| | - Emilia Severin
- Department of Genetics, University of Medicine and Pharmacy ”Carol Davila”, 020021 Bucharest, Romania
| | - Alexandru Daniel Jurca
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410081 Oradea, Romania
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Li B, Li W, Liu T, Zha L. Extracellular vesicles regulate the transmission of insulin resistance and redefine noncommunicable diseases. Front Mol Biosci 2023; 9:1024786. [PMID: 36699697 PMCID: PMC9868246 DOI: 10.3389/fmolb.2022.1024786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/19/2022] [Indexed: 01/10/2023] Open
Abstract
Noncommunicable diseases (NCDs), such as diabetes and related neurological disorders, are considered to not be directly transmissible from one person to another. However, NCDs may be transmissible in vivo through extracellular vesicles (EVs). A long-term high-fat diet (HFD) can induce a series of health issues like hyperlipidemia, type 2 diabetes mellitus (T2DM), and diabetic peripheral neuropathy (DPN) due to insulin resistance. Multiple molecular signaling changes can stimulate insulin resistance, especially blocking insulin signaling by increased insulin resistance inducer (phosphorylation of negative regulatory sites of insulin receptor substrate (IRS) proteins) and decreased tyrosine phosphorylation of insulin receptor substrate (phosphorylation of positive regulatory sites of IRS), thus leading to reduced phosphorylation of AKT enzymes. Current efforts to treat T2DM and prevent its complications mainly focus on improving insulin sensitivity, enhancing insulin secretion, or supplementing exogenous insulin based on a common assumption that insulin resistance is noncommunicable. However, insulin resistance is transmissible within multiple tissues or organs throughout the body. Exploring the regulatory roles of EVs in developing insulin resistance may provide novel and effective preventive and therapeutic strategies.
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Affiliation(s)
- Biao Li
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration Key Laboratory of Cosmetic Safety Evaluation, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
| | - Wan Li
- School of Physical Education, Hubei Minzu University, Enshi, China
| | - Tiancai Liu
- Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Longying Zha
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, National Medical Products Administration Key Laboratory of Cosmetic Safety Evaluation, School of Public Health, Southern Medical University, Guangzhou, Guangdong, China
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Aroor A, DeMarco VG, Whaley-Connell AT, Jia G, Yang Y, Sharma N, Naz H, Hans C, Hayden MR, Hill MA, Sowers JR, Manrique-Acevedo C, Lastra G. Endothelial cell-specific mineralocorticoid receptor activation promotes diastolic dysfunction in diet-induced obese male mice. Am J Physiol Regul Integr Comp Physiol 2023; 324:R90-R101. [PMID: 36440901 PMCID: PMC9799154 DOI: 10.1152/ajpregu.00274.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/17/2022] [Accepted: 11/17/2022] [Indexed: 11/30/2022]
Abstract
Widespread consumption of diets high in fat and fructose (Western diet, WD) has led to increased prevalence of obesity and diastolic dysfunction (DD). DD is a prominent feature of heart failure with preserved ejection fraction (HFpEF). However, the underlying mechanisms of DD are poorly understood, and treatment options are still limited. We have previously shown that deletion of the cell-specific mineralocorticoid receptor in endothelial cells (ECMR) abrogates DD induced by WD feeding in female mice. However, the specific role of ECMR activation in the pathogenesis of DD in male mice has not been clarified. Therefore, we fed 4-wk-old ECMR knockout (ECMRKO) male mice and littermates (LM) with either a WD or chow diet (CD) for 16 wk. WD feeding resulted in DD characterized by increased left ventricle (LV) filling pressure (E/e') and diastolic stiffness [E/e'/LV inner diameter at end diastole (LVIDd)]. Compared with CD, WD in LM resulted in increased myocardial macrophage infiltration, oxidative stress, and increased myocardial phosphorylation of Akt, in concert with decreased phospholamban phosphorylation. WD also resulted in focal cardiomyocyte remodeling, characterized by areas of sarcomeric disorganization, loss of mitochondrial electron density, and mitochondrial fragmentation. Conversely, WD-induced DD and associated biochemical and structural abnormalities were prevented by ECMR deletion. In contrast with our previously reported observations in females, WD-fed male mice exhibited enhanced Akt signaling and a lower magnitude of cardiac injury. Collectively, our data support a critical role for ECMR in obesity-induced DD and suggest critical mechanistic differences in the genesis of DD between males and females.
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Affiliation(s)
- Annayya Aroor
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Vincent G DeMarco
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Adam T Whaley-Connell
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Division of Nephrology, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Guanghong Jia
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Yan Yang
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Neekun Sharma
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Huma Naz
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
| | - Chetan Hans
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Melvin R Hayden
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
| | - Michael A Hill
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - James R Sowers
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Camila Manrique-Acevedo
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
- Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri
| | - Guido Lastra
- Division of Endocrinology and Metabolism, Department of Medicine, University of Missouri, Columbia, Missouri
- Research Service, Harry S. Truman Memorial Veterans Affairs Hospital, Columbia, Missouri
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10
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Qian G, Morral N. Role of non-coding RNAs on liver metabolism and NAFLD pathogenesis. Hum Mol Genet 2022; 31:R4-R21. [PMID: 35417923 DOI: 10.1093/hmg/ddac088] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/22/2022] [Accepted: 04/08/2022] [Indexed: 11/14/2022] Open
Abstract
Obesity and type 2 diabetes are major contributors to the growing prevalence of non-alcoholic fatty liver disease (NAFLD), a chronic liver condition characterized by the accumulation of fat in individuals without a significant amount of alcohol intake. The NAFLD spectrum ranges from simple steatosis (early stages, known as NAFL) to non-alcoholic steatohepatitis, which can progress to fibrosis and cirrhosis or hepatocellular carcinoma. Obesity, type 2 diabetes and NAFLD are strongly associated with insulin resistance. In the liver, insulin resistance increases hepatic glucose output, lipogenesis and very-low-density lipoprotein secretion, leading to a combination of hyperglycemia and hypertriglyceridemia. Aberrant gene expression is a hallmark of insulin resistance. Non-coding RNAs (ncRNAs) have emerged as prominent regulators of gene expression that operate at the transcriptional, post-transcriptional and post-translational levels. In the last couple of decades, a wealth of studies have provided evidence that most processes of liver metabolism are orchestrated by ncRNAs. This review focuses on the role of microRNAs, long non-coding RNAs and circular RNAs as coordinators of hepatic function, as well as the current understanding on how their dysregulation contributes to abnormal metabolism and pathophysiology in animal models of insulin resistance and NAFLD. Moreover, ncRNAs are emerging as useful biomarkers that may be able to discriminate between the different stages of NAFLD. The potential of ncRNAs as therapeutic drugs for NAFLD treatment and as biomarkers is discussed.
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Affiliation(s)
- Gene Qian
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Núria Morral
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
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11
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Lima YC, Krauczuk TT, Marmentini C, da Fonseca Alves G, Ferezini J, Piovan S, Gomes RM, Milani PG, da Costa SC, Mareze-Costa CE, Kurauti MA. Whey protein sweetened with Stevia rebaudiana increases insulin-degrading enzyme, but not carcinoembryonic antigen-related cell adhesion molecule 1 expression in the liver from resistance-trained rats. NUTRIRE 2022; 47:5. [DOI: 10.1186/s41110-022-00156-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 03/02/2022] [Indexed: 01/05/2025]
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12
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Rampin A, Carrabba M, Mutoli M, Eman CL, Testa G, Madeddu P, Spinetti G. Recent Advances in KEAP1/NRF2-Targeting Strategies by Phytochemical Antioxidants, Nanoparticles, and Biocompatible Scaffolds for the Treatment of Diabetic Cardiovascular Complications. Antioxid Redox Signal 2022; 36:707-728. [PMID: 35044251 DOI: 10.1089/ars.2021.0134] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Modulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated antioxidant response is a key aspect in the onset of diabetes-related cardiovascular complications. With this review, we provide an overview of the recent advances made in the development of Nrf2-targeting strategies for the treatment of diabetes, with particular attention toward the activation of Nrf2 by natural antioxidant compounds, nanoparticles, and oxidative stress-modulating biocompatible scaffolds. Recent Advances: In the past 30 years, studies addressing the use of antioxidant therapies to treat diabetes have grown exponentially, showing promising but yet inconclusive results. Animal studies and clinical trials on the Nrf2 pathway have shown promising results, suggesting that its activation can delay or reverse some of the cardiovascular impairments in diabetes. Critical Issues: Hyperglycemia- and oscillating glucose levels-induced reactive oxygen species (ROS) accumulation is progressively emerging as a central factor in the onset and progression of diabetes-related cardiovascular complications, including endothelial dysfunction, retinopathy, heart failure, stroke, critical limb ischemia, ulcers, and delayed wound healing. In this context, accumulating evidence suggests a central role for Nrf2-mediated antioxidant response, one of the most studied cellular defensive mechanisms against ROS accumulation. Future Directions: Innovative approaches such as tissue engineering and nanotechnology are converging toward targeting oxidative stress in diabetes. Antioxid. Redox Signal. 36, 707-728.
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Affiliation(s)
- Andrea Rampin
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, IRCCS MultiMedica, Milan, Italy
| | - Michele Carrabba
- Laboratory of Experimental Cardiovascular Medicine, University of Bristol, Bristol, England, United Kingdom
| | - Martina Mutoli
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, IRCCS MultiMedica, Milan, Italy
| | - Charlotte L Eman
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, IRCCS MultiMedica, Milan, Italy
| | - Gianluca Testa
- Department of Medicine and Health Sciences, "V. Tiberio" University of Molise, Campobasso, Italy.,Interdepartmental Center for Nanotechnology Research-NanoBem, University of Molise, Campobasso, Italy
| | - Paolo Madeddu
- Laboratory of Experimental Cardiovascular Medicine, University of Bristol, Bristol, England, United Kingdom
| | - Gaia Spinetti
- Laboratory of Cardiovascular Physiopathology-Regenerative Medicine, IRCCS MultiMedica, Milan, Italy
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13
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Lee JC, Kim JM, Joung KH, Kang SM, Kim HJ, Ku BJ. Serum MIG6 concentration is increased by cholesterol-lowering treatment in patients with type 2 diabetes mellitus and hypercholesterolemia. J Int Med Res 2022; 50:3000605221085079. [PMID: 35301888 PMCID: PMC8943322 DOI: 10.1177/03000605221085079] [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] [Indexed: 11/15/2022] Open
Abstract
Objective The protein encoded by mitogen-inducible gene 6 (MIG6) plays an essential role in the regulation of cholesterol homeostasis and bile acid synthesis in mice. However, the physiological functions of MIG6 remain poorly understood in humans. Therefore, we aimed to evaluate the relationship between the serum MIG6 concentration and low-density lipoprotein (LDL)-cholesterol in patients undergoing cholesterol-lowering treatment. Methods We performed a non-randomized, prospective controlled trial. In total, 63 patients with type 2 diabetes and hypercholesterolemia were treated using either rosuvastatin monotherapy or rosuvastatin/ezetimibe combination therapy for 12 weeks. We then compared their serum lipid and MIG6 concentrations before and after treatment. Results The serum LDL-cholesterol concentration of the participants significantly decreased and the concentration of MIG6 significantly increased during treatment. In addition, higher pre-treatment serum concentrations of MIG6 were associated with larger reductions in LDL-cholesterol, regardless of the therapeutic agent used. Conclusions Serum MIG6 concentration significantly increases alongside the reduction in LDL-cholesterol achieved using cholesterol-lowering therapies in patients with diabetes and hypercholesterolemia. This is the first study to provide evidence that MIG6 may be involved in human cholesterol metabolism. CRIS registration number: KCT0003477. https://cris.nih.go.kr.
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Affiliation(s)
- Jun Choul Lee
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon 35233, Republic of Korea
| | - Ji Min Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.,Department of Endocrinology, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Kyong Hye Joung
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea.,Department of Endocrinology, Chungnam National University Sejong Hospital, Sejong 30099, Republic of Korea
| | - Seon Mee Kang
- Department of Internal Medicine, Kangwon National University Hospital, Chuncheon 24289, Republic of Korea
| | - Hyun Jin Kim
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
| | - Bon Jeong Ku
- Department of Internal Medicine, Chungnam National University College of Medicine, Daejeon 35015, Republic of Korea
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14
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Carnosic Acid Attenuates the Free Fatty Acid-Induced Insulin Resistance in Muscle Cells and Adipocytes. Cells 2022; 11:cells11010167. [PMID: 35011728 PMCID: PMC8750606 DOI: 10.3390/cells11010167] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/10/2021] [Accepted: 12/28/2021] [Indexed: 12/12/2022] Open
Abstract
Elevated blood free fatty acids (FFAs), as seen in obesity, impair insulin action leading to insulin resistance and Type 2 diabetes mellitus. Several serine/threonine kinases including JNK, mTOR, and p70 S6K cause serine phosphorylation of the insulin receptor substrate (IRS) and have been implicated in insulin resistance. Activation of AMP-activated protein kinase (AMPK) increases glucose uptake, and in recent years, AMPK has been viewed as an important target to counteract insulin resistance. We reported previously that carnosic acid (CA) found in rosemary extract (RE) and RE increased glucose uptake and activated AMPK in muscle cells. In the present study, we examined the effects of CA on palmitate-induced insulin-resistant L6 myotubes and 3T3L1 adipocytes. Exposure of cells to palmitate reduced the insulin-stimulated glucose uptake, GLUT4 transporter levels on the plasma membrane, and Akt activation. Importantly, CA attenuated the deleterious effect of palmitate and restored the insulin-stimulated glucose uptake, the activation of Akt, and GLUT4 levels. Additionally, CA markedly attenuated the palmitate-induced phosphorylation/activation of JNK, mTOR, and p70S6K and activated AMPK. Our data indicate that CA has the potential to counteract the palmitate-induced muscle and fat cell insulin resistance.
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15
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Rubina KA, Semina EV, Kalinina NI, Sysoeva VY, Balatskiy AV, Tkachuk VA. Revisiting the multiple roles of T-cadherin in health and disease. Eur J Cell Biol 2021; 100:151183. [PMID: 34798557 DOI: 10.1016/j.ejcb.2021.151183] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 01/02/2023] Open
Abstract
As a non-canonical member of cadherin superfamily, T-cadherin was initially described as a molecule involved in homophilic recognition in the nervous and vascular systems. The ensuing decades clearly demonstrated that T-cadherin is a remarkably multifunctional molecule. It was validated as a bona fide receptor for both: LDL exerting adverse atherogenic action and adiponectin mediating many protective metabolic and cardiovascular effects. Motivated by the latest progress and accumulated data unmasking important roles of T-cadherin in blood vessel function and tissue regeneration, here we revisit the original function of T-cadherin as a guidance receptor for the growing axons and blood vessels, consider the recent data on T-cadherin-induced exosomes' biogenesis and their role in myocardial regeneration and revascularization. The review expands upon T-cadherin contribution to mesenchymal stem/stromal cell compartment in adipose tissue. We also dwell upon T-cadherin polymorphisms (SNP) and their possible therapeutic applications. Furthermore, we scrutinize the molecular hub of insulin and adiponectin receptors (AdipoR1 and AdipoR2) conveying signals to their downstream targets in quest for defining a putative place of T-cadherin in this molecular circuitry.
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Affiliation(s)
- K A Rubina
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia.
| | - E V Semina
- Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, 121552 Moscow, Russia
| | - N I Kalinina
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia
| | - V Yu Sysoeva
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia
| | - A V Balatskiy
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia
| | - V A Tkachuk
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; Institute of Experimental Cardiology, National Cardiology Research Center of the Ministry of Health of the Russian Federation, 121552 Moscow, Russia
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16
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O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021; 12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.
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Affiliation(s)
| | - Selina Uranga
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| | - James D Fluckey
- Health and Kinesiology, Texas A&M University, TX 77843, United States
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17
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Evangelista-Silva PH, Prates RP, Leite JSM, Moreno LG, Goulart-Silva F, Esteves EA. Intestinal GLUT5 and FAT/CD36 transporters and blood glucose are reduced by a carotenoid/MUFA-rich oil in high-fat fed mice. Life Sci 2021; 279:119672. [PMID: 34097971 DOI: 10.1016/j.lfs.2021.119672] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 10/21/2022]
Abstract
AIMS Intestinal nutrient absorption plays a vital role in developing obesity, and nutrient transporters expressed in the enterocytes facilitate this process. Moreover, previous studies have shown that specific foods and diets can affect their cell levels. Herein, we investigated the effects of pequi oil (PO), which is high in several bioactive compounds, on intestinal nutrient transporter levels as well as on intestinal morphology and metabolic biomarkers. MAIN METHODS Groups of male C57BL/6 mice were fed either a standard (C) or a high-fat diet (HFD) and pequi oil (CP and HFDP with PO by gavage at 150 mg/day) for eight weeks. Food intake and body weight were monitored, serum metabolic biomarkers, intestinal transporter levels and histological analyses were performed. KEY FINDINGS PO increased caloric intake without increasing body or fat mass regardless of diet. The HFD group treated with PO reduced fasting blood glucose and villus width. PO did not affect GLUT2, L-FABP, FATP4, NPC1L1, NHE3 or PEPT1 content in CP or HFDP groups. GLUT5 and FAT/CD36 levels were reduced in both CP and HFDP. SIGNIFICANCE Our data suggest that PO attenuated monosaccharide and fatty acid absorption, contributing to lower fasting glycemia and higher food intake without affecting body weight or visceral fat of high-fat feed mice.
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Affiliation(s)
- Paulo Henrique Evangelista-Silva
- Faculty of Biological and Health Sciences, Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri - UFVJM, Rodovia MGT 367 - Km 583. n. 5000, Alto da Jacuba, Diamantina, MG 39100-000, Brazil; Institute of Biomedical Sciences, Department of Physiology and Biophysics, Universidade de São Paulo - USP, Av. Prof. Dr. Lineu Prestes. 1524, Butantã, São Paulo, SP 05508-000, Brazil
| | - Rodrigo Pereira Prates
- Faculty of Biological and Health Sciences, Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri - UFVJM, Rodovia MGT 367 - Km 583. n. 5000, Alto da Jacuba, Diamantina, MG 39100-000, Brazil
| | - Jaqueline Santos Moreira Leite
- Institute of Biomedical Sciences, Department of Physiology and Biophysics, Universidade de São Paulo - USP, Av. Prof. Dr. Lineu Prestes. 1524, Butantã, São Paulo, SP 05508-000, Brazil
| | - Lauane Gomes Moreno
- Faculty of Biological and Health Sciences, Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri - UFVJM, Rodovia MGT 367 - Km 583. n. 5000, Alto da Jacuba, Diamantina, MG 39100-000, Brazil
| | - Francemilson Goulart-Silva
- Institute of Biomedical Sciences, Department of Physiology and Biophysics, Universidade de São Paulo - USP, Av. Prof. Dr. Lineu Prestes. 1524, Butantã, São Paulo, SP 05508-000, Brazil
| | - Elizabethe Adriana Esteves
- Faculty of Biological and Health Sciences, Programa de Pós-Graduação Multicêntrico em Ciências Fisiológicas, Universidade Federal dos Vales do Jequitinhonha e Mucuri - UFVJM, Rodovia MGT 367 - Km 583. n. 5000, Alto da Jacuba, Diamantina, MG 39100-000, Brazil.
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18
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Kuramoto K, Kim YJ, Hong JH, He C. The autophagy protein Becn1 improves insulin sensitivity by promoting adiponectin secretion via exocyst binding. Cell Rep 2021; 35:109184. [PMID: 34038729 PMCID: PMC8177967 DOI: 10.1016/j.celrep.2021.109184] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 03/16/2021] [Accepted: 05/05/2021] [Indexed: 12/14/2022] Open
Abstract
Autophagy dysregulation is implicated in metabolic diseases, including type 2 diabetes. However, the mechanism by which the autophagy machinery regulates metabolism is largely unknown. Autophagy is generally considered a degradation process via lysosomes. Here, we unveil a metabolically important non-cell-autonomous, non-degradative mechanism regulated by the essential autophagy protein Becn1 in adipose tissue. Upon high-fat diet challenge, autophagy-hyperactive Becn1F121A mice show systemically improved insulin sensitivity and enhanced activation of AMP-activated protein kinase (AMPK), a central regulator of energy homeostasis, via a non-cell-autonomous mechanism mediated by adiponectin, an adipose-derived metabolic hormone. Adipose-specific Becn1F121A expression is sufficient to activate AMPK in non-adipose tissues and improve systemic insulin sensitivity by increasing adiponectin secretion. Further, Becn1 enhances adiponectin secretion by interacting with components of the exocyst complex via the coiled-coil domain. Together, our study demonstrates that Becn1 improves insulin sensitivity by facilitating adiponectin secretion through binding the exocyst in adipose tissue.
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Affiliation(s)
- Kenta Kuramoto
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yoon-Jin Kim
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Jung Hwa Hong
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Congcong He
- Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
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19
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Li Z, Hu Z, Meng Y, Xu H, Wei Y, Shen D, Bai H, Yuan H, Chen L. miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats. PeerJ 2021; 9:e10920. [PMID: 33868799 PMCID: PMC8029671 DOI: 10.7717/peerj.10920] [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: 09/28/2020] [Accepted: 01/19/2021] [Indexed: 11/28/2022] Open
Abstract
Background Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. Material and Methods Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. Results We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. Conclusion miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.
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Affiliation(s)
- Zhaoping Li
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,Department of Clinical Nutrition, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhenzhen Hu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yan Meng
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,Department of Clinical Nutrition, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Hongzhao Xu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yali Wei
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Deqiang Shen
- Department of Clinical Nutrition, Lianyungang Hospital Affiliated to Xuzhou Medical University, Lianyungang, Jiangsu, China
| | - Hao Bai
- Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China
| | - Huacai Yuan
- Department of Clinical Nutrition, Qingdao Municipal Hospital, Qingdao, Shandong, China
| | - Liyong Chen
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.,Department of Clinical Nutrition, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
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20
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Abstract
Aging is characterized by a progressive loss of physiological function leading to increase in the vulnerability to death. This deterioration process occurs in all living organisms and is the primary risk factor for pathological conditions including obesity, type 2 diabetes mellitus, Alzheimer's disease and cardiovascular diseases. Most of the age-related diseases have been associated with impairment of action of an important hormone, namely insulin. It is well-known that this hormone is a critical mediator of metabolism, growth, proliferation and differentiation. Insulin action depends on two processes that determine its circulating levels, insulin secretion and clearance, and insulin sensitivity in its target tissues. Aging has deleterious effects on these three mechanisms, impairing insulin action, thereby increasing the risk for diseases and death. Thus, improving insulin action may be an important strategy to have a healthier and longer life.
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21
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Shamshoum H, Vlavcheski F, MacPherson REK, Tsiani E. Rosemary extract activates AMPK, inhibits mTOR and attenuates the high glucose and high insulin-induced muscle cell insulin resistance. Appl Physiol Nutr Metab 2021; 46:819-827. [PMID: 33471600 DOI: 10.1139/apnm-2020-0592] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Impaired action of insulin in skeletal muscle, termed insulin resistance, leads to increased blood glucose levels resulting in compensatory increase in insulin levels. The elevated blood glucose and insulin levels exacerbate insulin resistance and contribute to the pathogenesis of type 2 diabetes mellitus. In previous studies we found attenuation of free fatty acid-induced muscle cell insulin resistance by rosemary extract (RE). In the present study we investigated the effects of RE on high glucose (HG) and high insulin (HI)-induced muscle cell insulin resistance. Exposure of L6 myotubes to 25 mmol/L glucose and 100 nmol/L insulin for 24 h, to mimic hyperglycemia and hyperinsulinemia, abolished the acute insulin-stimulated glucose uptake, increased the serine phosphorylation of IRS-1 and the phosphorylation/activation of mTOR and p70S6K. Treatment with RE significantly improved the insulin-stimulated glucose uptake and increased the acute insulin-stimulated tyrosine phosphorylation while reducing the HG+HI-induced serine phosphorylation of IRS-1 and phosphorylation of mTOR and p70S6K. Additionally, treatment with RE significantly increased the phosphorylation of AMPK, its downstream effector ACC and the plasma membrane GLUT4 levels. Our data indicate a potential of RE to counteract muscle cell insulin resistance and more studies are required to investigate its effectiveness in vivo. Novelty: RE phosphorylated muscle cell AMPK and ACC under both normal and HG+HI conditions. The HG+HI-induced serine phosphorylation of IRS-1 and activation of mTOR and p70S6K were attenuated by RE. RE restored the insulin-stimulated glucose uptake by enhancing GLUT4 glucose transporter translocation to plasma membrane.
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Affiliation(s)
- Hesham Shamshoum
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Filip Vlavcheski
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON, Canada.,Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada
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22
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Haas de Mello A, Ferreira GK, Rezin GT. Abnormal mitochondrial metabolism in obesity and insulin resistance. CLINICAL BIOENERGETICS 2021:83-92. [DOI: 10.1016/b978-0-12-819621-2.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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23
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Morales-Scholz MG, Swinton C, Murphy RM, Kowalski GM, Bruce CR, Howlett KF, Shaw CS. Autophagy is not involved in lipid accumulation and the development of insulin resistance in skeletal muscle. Biochem Biophys Res Commun 2021; 534:533-539. [PMID: 33261883 DOI: 10.1016/j.bbrc.2020.11.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 11/12/2020] [Indexed: 01/15/2023]
Abstract
OBJECTIVE To investigate the effect of high fat diet-induced insulin resistance on autophagy markers in the liver and skeletal muscle of mice in the fasted state and following an oral glucose bolus. METHODS Forty C57BL/6J male mice were fed either a high fat, high sucrose (HFSD, n = 20) or standard chow control (CON, n = 20) diet for 16 weeks. Upon trial completion, mice were gavaged with water or glucose and skeletal muscle and liver were collected 15 min post gavage. Protein abundance and gene expression of autophagy markers and activation of related signalling pathways were assessed. RESULTS Compared to CON, the HFSD intervention increased LC3B-II and p62/SQSTM1 protein abundance in the liver which is indicative of elevated autophagosome content via reduced clearance. These changes coincided with inhibitory autophagy signalling through elevated p-mTOR S2448 and p-ULK1S758. HFSD did not alter autophagy markers in skeletal muscle. Administration of an oral glucose bolus had no effect on autophagy markers or upstream signalling responses in either tissue regardless of diet. CONCLUSION HFSD induces tissue-specific autophagy impairments, with autophagosome accumulation indicating reduced lysosomal clearance in the liver. In contrast, autophagy markers were unchanged in skeletal muscle, indicating that autophagy is not involved in the development of skeletal muscle insulin resistance.
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Affiliation(s)
- María G Morales-Scholz
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia
| | - Courtney Swinton
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia
| | - Robyn M Murphy
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, 3086, VIC, Australia
| | - Greg M Kowalski
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia
| | - Clinton R Bruce
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia
| | - Kirsten F Howlett
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia
| | - Christopher S Shaw
- Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Geelong, 3216, VIC, Australia.
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24
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Li Z, Shen D, Meng Y, Xu H, Yuan H, Chen L. miR-155-5p alleviates ethanol-induced myocardial insulin resistance in H9C2 cells via regulating the mTOR signalling pathway. Mol Biol Rep 2020; 47:9469-9477. [PMID: 33159675 DOI: 10.1007/s11033-020-05967-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 10/30/2020] [Indexed: 01/12/2023]
Abstract
Alcohol exposure impairs myocardium insulin sensitivity, which links to heart dysfunction. miR-155 regulates mTOR signaling pathway and is involved in multiple functions. However, the underlying mechanism of miR-155 in ethanol-induced myocardial insulin resistance remains unclear. Here, in this study we aimed to identify the role of miR-155 in myocardial insulin sensitivity and the involvement of mTOR pathway. H9C2 cells were cultured with or without 100 mM ethanol for 24 h. miR-155-5p inhibitor, miR-155-5p mimics or their respective negative control (inhibitor NC and mimic NC) were transfected to regulate miR-155-5p expression. mTOR signaling, including Ras homolog enriched in brain (Rheb), rapamycin insensitive companion of mTOR (Rictor) and ribosomal protein S6 kinase B2 (S6K2), was investigated by western blotting and qPCR, and insulin responsiveness was evaluated by glucose uptake and phosphorylation of insulin receptor substrate-1 (p-IRS1). The miR-155-5p level increased under ethanol exposure, accompanied by a decrease in glucose uptake, an increase in p-IRS1(ser 307) and activation of the mTOR signaling pathway in H9C2 cells. In addition, miR-155-5p downregulation decreased the glucose uptake, increased the p-IRS1(ser 307) level and activated the mTOR signaling pathway. miR-155-5p upregulation increased the glucose uptake, decreased the p-IRS1(ser 307) level and suppressed the mTOR signaling pathway. Collectively, these findings suggest miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in vitro, and miR-155-5p downregulation attenuates myocardial insulin resistance, which might become a potential therapeutic target for alcohol-induced cardiomyopathy.
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Affiliation(s)
- Zhaoping Li
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, Shandong, China
| | - Deqiang Shen
- Department of Clinical Nutrition, Lianyungang Hospital Affiliated to Xuzhou Medical University, Lianyungang, 222061, Jiangsu, China
| | - Yan Meng
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, Shandong, China
| | - Hongzhao Xu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, 250024, Shandong, China
| | - Huacai Yuan
- Department of Clinical Nutrition, Qingdao Municipal Hospital, Qingdao, 266000, Shandong, China
| | - Liyong Chen
- Department of Clinical Nutrition, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan, 250021, Shandong, China. .,Department of Clinical Nutrition, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, 324 Jingwu Road, Jinan, 250021, Shandong, China.
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Martínez-Cué C, Rueda N. Signalling Pathways Implicated in Alzheimer's Disease Neurodegeneration in Individuals with and without Down Syndrome. Int J Mol Sci 2020; 21:E6906. [PMID: 32962300 PMCID: PMC7555886 DOI: 10.3390/ijms21186906] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023] Open
Abstract
Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer's disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.
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Affiliation(s)
- Carmen Martínez-Cué
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, 39011 Santander, Spain;
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Autophagy and mTOR Pathways Mediate the Potential Renoprotective Effects of Vitamin D on Diabetic Nephropathy. Int J Nephrol 2020; 2020:7941861. [PMID: 32455017 PMCID: PMC7243019 DOI: 10.1155/2020/7941861] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Introduction Not only is diabetic nephropathy (DN) the most common cause of end-stage renal disease worldwide, but it also increases the risk of mortality up to fourteen times compared to normoalbuminuric diabetic patients. Aim The aim of the current study was the evaluation of the renoprotective effects of vitamin D in DN and the possible interplay between autophagy and mTOR pathways. Materials and Methods Fifty male Wistar albino rats were divided (10/group) into control, DN group, insulin-treated DN group, vitamin D-treated DN group, and combined insulin and vitamin D-treated DN group. Assessments of systolic blood pressure, albuminuria, creatinine clearance, serum glucose, insulin, urea, creatinine, inflammatory cytokines, oxidative stress markers, and rat kidney gene expression of mTOR were performed. Histopathological and immunohistochemical assessments of autophagy marker LC3 in rat kidneys were also performed. Results DN was associated with significant increases in SBP, urinary albumin, serum glucose, urea, creatinine, inflammatory cytokines, MDA, and mTOR gene expression (P < 0.05). However, there was significant decrease in creatinine clearance, serum insulin, GSH, and H score value of LC3 when compared with control group (P < 0.05). The combination of insulin and vitamin D treatment significantly restored DN changes when compared with the other treated groups, except in oxidative stress markers where there was an insignificant difference between the combination-treated and insulin-treated groups (P > 0.05). Conclusion It has been concluded that vitamin D is a potent adjuvant therapy in treatment of DN via downregulation of mTOR gene expression, stimulation of autophagy, and antioxidant, anti-inflammatory, and hypotensive effects.
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Vlavcheski F, Den Hartogh DJ, Giacca A, Tsiani E. Amelioration of High-Insulin-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol Is Linked to Activation of AMPK and Restoration of GLUT4 Translocation. Nutrients 2020; 12:E914. [PMID: 32230718 PMCID: PMC7230755 DOI: 10.3390/nu12040914] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/17/2020] [Accepted: 03/23/2020] [Indexed: 12/14/2022] Open
Abstract
Insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM), is linked to hyperinsulinemia, which develops to counterbalance initial peripheral hormone resistance. Studies indicate that chronically elevated levels of insulin lead to skeletal muscle insulin resistance by deregulating steps within the insulin signaling cascade. The polyphenol resveratrol (RSV) has been shown to have antidiabetic properties in vitro and in vivo. In the present study, we examined the effect of RSV on high insulin (HI)-induced insulin resistance in skeletal muscle cells in vitro and investigated the mechanisms involved. Parental and GLUT4myc-overexpressing L6 rat skeletal muscle cells were used. [3H]2-deoxyglucose (2DG) uptake was measured, and total and phosphorylated levels of specific proteins were examined by immunoblotting. Exposure of L6 cells to HI levels (100 nM) for 24 h decreased the acute-insulin-stimulated 2DG uptake, indicating insulin resistance. HI increased ser307 and ser636/639 phosphorylation of IRS-1 (to 184% ± 12% and 225% ± 28.9% of control, with p < 0.001 and p < 0.01, respectively) and increased the phosphorylation levels of mTOR (174% ± 6.7% of control, p < 0.01) and p70 S6K (228% ± 33.5% of control, p < 0.01). Treatment with RSV abolished these HI-induced responses. Furthermore, RSV increased the activation of AMPK and restored the insulin-mediated increase in plasma membrane GLUT4 glucose transporter levels. These data suggest that RSV has a potential to counteract the HI-induced muscle insulin resistance.
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Affiliation(s)
- Filip Vlavcheski
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (F.V.); (D.J.D.H.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Danja J. Den Hartogh
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (F.V.); (D.J.D.H.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Adria Giacca
- Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada;
- Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8T, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, ON M5G 2C4, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (F.V.); (D.J.D.H.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
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Anti-aging Effects of Calorie Restriction (CR) and CR Mimetics based on the Senoinflammation Concept. Nutrients 2020; 12:nu12020422. [PMID: 32041168 PMCID: PMC7071238 DOI: 10.3390/nu12020422] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/29/2020] [Accepted: 02/03/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation, a pervasive feature of the aging process, is defined by a continuous, multifarious, low-grade inflammatory response. It is a sustained and systemic phenomenon that aggravates aging and can lead to age-related chronic diseases. In recent years, our understanding of age-related chronic inflammation has advanced through a large number of investigations on aging and calorie restriction (CR). A broader view of age-related inflammation is the concept of senoinflammation, which has an outlook beyond the traditional view, as proposed in our previous work. In this review, we discuss the effects of CR on multiple phases of proinflammatory networks and inflammatory signaling pathways to elucidate the basic mechanism underlying aging. Based on studies on senoinflammation and CR, we recognized that senescence-associated secretory phenotype (SASP), which mainly comprises cytokines and chemokines, was significantly increased during aging, whereas it was suppressed during CR. Further, we recognized that cellular metabolic pathways were also dysregulated in aging; however, CR mimetics reversed these effects. These results further support and enhance our understanding of the novel concept of senoinflammation, which is related to the metabolic changes that occur in the aging process. Furthermore, a thorough elucidation of the effect of CR on senoinflammation will reveal key insights and allow possible interventions in aging mechanisms, thus contributing to the development of new therapies focused on improving health and longevity.
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Blagosklonny MV. Rapamycin for longevity: opinion article. Aging (Albany NY) 2019; 11:8048-8067. [PMID: 31586989 PMCID: PMC6814615 DOI: 10.18632/aging.102355] [Citation(s) in RCA: 133] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Accepted: 10/03/2019] [Indexed: 12/31/2022]
Abstract
From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.
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Bernasconi P, Carboni N, Ricci G, Siciliano G, Politano L, Maggi L, Mongini T, Vercelli L, Rodolico C, Biagini E, Boriani G, Ruggiero L, Santoro L, Schena E, Prencipe S, Evangelisti C, Pegoraro E, Morandi L, Columbaro M, Lanzuolo C, Sabatelli P, Cavalcante P, Cappelletti C, Bonne G, Muchir A, Lattanzi G. Elevated TGF β2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes. Nucleus 2019; 9:292-304. [PMID: 29693488 PMCID: PMC5973167 DOI: 10.1080/19491034.2018.1467722] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.
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Affiliation(s)
- Pia Bernasconi
- a Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit , Foundation IRCCS Neurological Institute "Carlo Besta" , Milan , Italy
| | - Nicola Carboni
- b Neurology Department , Hospital San Francesco of Nuoro , Nuoro , Italy
| | - Giulia Ricci
- c Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Gabriele Siciliano
- c Department of Clinical and Experimental Medicine , University of Pisa , Pisa , Italy
| | - Luisa Politano
- d Cardiomyology and Medical Genetics, Department of Experimental Medicine , Campania University "Luigi Vanvitelli" (former denomination: Second University of Naples) , Italy
| | - Lorenzo Maggi
- a Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit , Foundation IRCCS Neurological Institute "Carlo Besta" , Milan , Italy
| | - Tiziana Mongini
- e Department of Neurosciences "Rita Levi Montalcini" , University of Turin , Turin , Italy
| | - Liliana Vercelli
- e Department of Neurosciences "Rita Levi Montalcini" , University of Turin , Turin , Italy
| | - Carmelo Rodolico
- f Institute of Applied Sciences and Intelligent Systems "ISASI Edoardo Caianello", National Research Council of Italy , Messina , Italy
| | - Elena Biagini
- g Istituto di Cardiologia, Università di Bologna, Policlinico S.Orsola-Malpighi , Bologna , Italy
| | - Giuseppe Boriani
- h Cardiology Division, Department of Diagnostics , Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Policlinico di Modena , Modena , Italy
| | - Lucia Ruggiero
- i Department of Neurosciences , Odontostomatological and Reproductive Sciences, University of Naples "Federico II" , Naples , Italy
| | - Lucio Santoro
- i Department of Neurosciences , Odontostomatological and Reproductive Sciences, University of Naples "Federico II" , Naples , Italy
| | - Elisa Schena
- j Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna , Bologna , Italy.,k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
| | - Sabino Prencipe
- j Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna , Bologna , Italy.,k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
| | - Camilla Evangelisti
- j Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna , Bologna , Italy.,k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
| | - Elena Pegoraro
- l Department of Neurosciences , Neuromuscular Center, University of Padova , Padova , Italy
| | - Lucia Morandi
- a Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit , Foundation IRCCS Neurological Institute "Carlo Besta" , Milan , Italy
| | - Marta Columbaro
- k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
| | - Chiara Lanzuolo
- m Istituto Nazionale di Genetica Molecolare "Romeo and Enrica Invernizzi" , Milan , Italy.,n Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia Foundation , Rome , Italy
| | - Patrizia Sabatelli
- j Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna , Bologna , Italy.,k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
| | - Paola Cavalcante
- a Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit , Foundation IRCCS Neurological Institute "Carlo Besta" , Milan , Italy
| | - Cristina Cappelletti
- a Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit , Foundation IRCCS Neurological Institute "Carlo Besta" , Milan , Italy
| | - Gisèle Bonne
- o Sorbonne Universités , UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière , Paris Cedex 13, France
| | - Antoine Muchir
- o Sorbonne Universités , UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, G.H. Pitié Salpêtrière , Paris Cedex 13, France
| | - Giovanna Lattanzi
- j Institute of Molecular Genetics (IGM)-CNR, Unit of Bologna , Bologna , Italy.,k Laboratory of Musculoskeletal Cell Biology , Rizzoli Orthopaedic Institute , Bologna , Italy
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Fasting and rapamycin: diabetes versus benevolent glucose intolerance. Cell Death Dis 2019; 10:607. [PMID: 31406105 PMCID: PMC6690951 DOI: 10.1038/s41419-019-1822-8] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 07/17/2019] [Indexed: 02/06/2023]
Abstract
Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.
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Abstract
Designed a century ago to treat epilepsy, the ketogenic diet (KD) is also effective against obesity and diabetes. Paradoxically, some studies in rodents have found that the KD seemingly causes diabetes, contradicting solid clinical data in humans. This paradox can be resolved by applying the concept of starvation pseudo-diabetes, which was discovered in starved animals almost two centuries ago, and has also been observed in some rapamycin-treated rodents. Intriguingly, use of the KD and rapamycin is indicated for a similar spectrum of diseases, including Alzheimer's disease and cancer. Even more intriguingly, benevolent (starvation) pseudo-diabetes may counteract type 2 diabetes or its complications.
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Oakie A, Feng ZC, Li J, Silverstein J, Yee SP, Wang R. Long-term c-Kit overexpression in beta cells compromises their function in ageing mice. Diabetologia 2019; 62:1430-1444. [PMID: 31154478 DOI: 10.1007/s00125-019-4890-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 04/04/2019] [Indexed: 12/23/2022]
Abstract
AIMS/HYPOTHESIS c-Kit signalling regulates intracellular pathways that enhance beta cell proliferation, insulin secretion and islet vascularisation in mice up to 28 weeks of age and on short-term high-fat diet. However, long-term c-Kit activation in ageing mouse islets has yet to be examined. This study utilises beta cell-specific c-Kit-overexpressing transgenic (c-KitβTg) ageing mice (~60 weeks) to determine the effect of its activation on beta cell dysfunction and insulin secretion. METHODS Wild-type and c-KitβTg mice, aged 60 weeks, were examined using metabolic tests to determine glucose tolerance and insulin secretion. Pancreas histology and proteins in isolated islets were examined to determine the expression of beta cell transcription factors, proliferation and intracellular signalling. To determine the role of insulin receptor signalling in ageing c-KitβTg mice, we generated beta cell-specific inducible insulin receptor knockout in ageing c-KitβTg mice (c-KitβTg;βIRKO mice) and examined the ageing mice for glucose tolerance and islet histology. RESULTS Ageing c-KitβTg mice progressively developed glucose intolerance, compared with age-matched wild-type littermates, due to impaired insulin secretion. Increased beta cell mass, proliferation and nuclear forkhead box transcription factor O1 (FOXO1) expression and reduced exocytotic protein levels were detected in ageing c-KitβTg mouse islets. Protein analyses of isolated islets showed increased insulin receptor, phosphorylated IRS-1Ser612 and cleaved poly(ADP-ribose) polymerase levels in ageing c-KitβTg mice. Ageing c-KitβTg mouse islets treated ex vivo with insulin demonstrated reduced Akt phosphorylation, indicating that prolonged c-Kit induced beta cell insulin insensitivity. Ageing c-KitβTg;βIRKO mice displayed improved glucose tolerance and beta cell function compared with ageing c-KitβTg mice. CONCLUSIONS/INTERPRETATION These findings indicate that long-term c-Kit overexpression in beta cells has a negative impact on insulin exocytosis and that temporally dependent regulation of c-Kit-insulin receptor signalling is important for optimal beta cell function.
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Affiliation(s)
- Amanda Oakie
- Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, N6C 2V5, Canada
- Department of Pathology and Laboratory Medicine, University of Western Ontario, London, ON, Canada
| | - Zhi-Chao Feng
- Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, N6C 2V5, Canada
| | - Jinming Li
- Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, N6C 2V5, Canada
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada
| | - Jenna Silverstein
- Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, N6C 2V5, Canada
| | - Siu-Pok Yee
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA
- Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT, USA
| | - Rennian Wang
- Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, Room A5-140, 800 Commissioners Road East, London, ON, N6C 2V5, Canada.
- Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
- Department of Medicine, University of Western Ontario, London, ON, Canada.
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de Mello NP, Orellana AM, Mazucanti CH, de Morais Lima G, Scavone C, Kawamoto EM. Insulin and Autophagy in Neurodegeneration. Front Neurosci 2019; 13:491. [PMID: 31231176 PMCID: PMC6558407 DOI: 10.3389/fnins.2019.00491] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 04/29/2019] [Indexed: 12/12/2022] Open
Abstract
Crosstalk in the pathophysiological processes underpinning metabolic diseases and neurodegenerative disorders have been the subject of extensive investigation, in which insulin signaling and autophagy impairment demonstrate to be a common factor in both conditions. Although it is still somewhat conflicting, pharmacological and genetic strategies that regulate these pathways may be a promising approach for aggregate protein clearancing and consequently the delaying of onset or progression of the disease. However, as the response due to this modulation seems to be time-dependent, finding the right regulation of autophagy may be a potential target for drug development for neurodegenerative diseases. In this way, this review focuses on the role of insulin signaling/resistance and autophagy in some neurodegenerative diseases, discussing pharmacological and non-pharmacological interventions in these diseases.
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Affiliation(s)
- Natália Prudente de Mello
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ana Maria Orellana
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Caio Henrique Mazucanti
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Geovanni de Morais Lima
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Cristoforo Scavone
- Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Elisa Mitiko Kawamoto
- Laboratory of Molecular and Functional Neurobiology, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Chiarini F, Evangelisti C, Lattanzi G, McCubrey JA, Martelli AM. Advances in understanding the mechanisms of evasive and innate resistance to mTOR inhibition in cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:1322-1337. [PMID: 30928610 DOI: 10.1016/j.bbamcr.2019.03.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/12/2022]
Abstract
The development of drug-resistance by neoplastic cells is recognized as a major cause of targeted therapy failure and disease progression. The mechanistic (previously mammalian) target of rapamycin (mTOR) is a highly conserved Ser/Thr kinase that acts as the catalytic subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. Both mTORC1 and mTORC2 play key roles in a variety of healthy cell types/tissues by regulating physiological anabolic and catabolic processes in response to external cues. However, a body of evidence identified aberrant activation of mTOR signaling as a common event in many human tumors. Therefore, mTOR is an attractive target for therapeutic targeting in cancer and this fact has driven the development of numerous mTOR inhibitors, several of which have progressed to clinical trials. Nevertheless, mTOR inhibitors have met with a very limited success as anticancer therapeutics. Among other reasons, this failure was initially ascribed to the activation of several compensatory signaling pathways that dampen the efficacy of mTOR inhibitors. The discovery of these regulatory feedback mechanisms greatly contributed to a better understanding of cancer cell resistance to mTOR targeting agents. However, over the last few years, other mechanisms of resistance have emerged, including epigenetic alterations, compensatory metabolism rewiring and the occurrence of mTOR mutations. In this article, we provide the reader with an updated overview of the mechanisms that could explain resistance of cancer cells to the various classes of mTOR inhibitors.
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Affiliation(s)
- Francesca Chiarini
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - Camilla Evangelisti
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - Giovanna Lattanzi
- CNR Institute of Molecular Genetics, 40136 Bologna, BO, Italy; IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, BO, Italy
| | - James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
| | - Alberto M Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, BO, Italy.
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Waise TMZ, Rasti M, Duca FA, Zhang SY, Bauer PV, Rhodes CJ, Lam TKT. Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production. Nat Commun 2019; 10:714. [PMID: 30755615 PMCID: PMC6372624 DOI: 10.1038/s41467-019-08582-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/16/2019] [Indexed: 12/11/2022] Open
Abstract
Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR. The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
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Affiliation(s)
- T M Zaved Waise
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Mozhgan Rasti
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Frank A Duca
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada.,School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, 85721, USA
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Paige V Bauer
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada.,Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Christopher J Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL, 60637, USA.,MedImmune LLC, Gaithersburg, MD, 20878, USA
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada. .,Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, M5G 2C4, Canada.
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Phan K, Charlton O, Smith SD. Hidradenitis suppurativa and diabetes mellitus: updated systematic review and adjusted meta-analysis. Clin Exp Dermatol 2019; 44:e126-e132. [PMID: 30730068 DOI: 10.1111/ced.13922] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/14/2018] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hidradenitis suppurativa (HS) is a debilitating and distressing chronic inflammatory skin disease. There is also evolving evidence supporting the association between HS and cardiovascular risk factors, including smoking, obesity, hyperlipidaemia and metabolic syndrome. Notably, these are clinical features and risk factors that are closely associated with type 2 diabetes mellitus (DM). AIMS We performed a pooled adjusted meta-analysis of comparative studies to investigate the relationship between HS and DM. METHODS A systematic review and meta-analysis was performed according to recommended Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. OR was used as the summary effect size. RESULTS From pooled analysis of unadjusted data from 12 studies, we found a significantly higher proportion of DM in HS cases compared with non-HS healthy controls (16.1% vs. 15.7%; OR = 2.17; 95% CI 1.85-2.55; P < 0.001). Adjusted effect sizes from five studies were also pooled. A significantly higher proportion of DM was found for HS compared with healthy controls, although the effect size was attenuated compared with unadjusted analyses (OR 1.69; 95% CI 1.50-1.91; P < 0.001). CONCLUSIONS To our knowledge, our systematic review and meta-analysis is the first to pool adjusted effect sizes. We found that HS was associated with a 1.69-fold increased odds of diabetes; however, the absolute risk difference was small (16.1% vs. 15.7%) and is probably not clinically relevant. Treating clinicians should be aware of this association, but there may not be an urgent need to perform screening for impaired glucose tolerance or diabetes.
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Affiliation(s)
- K Phan
- Department of Dermatology, Liverpool Hospital, Liverpool, Sydney, Australia.,Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - O Charlton
- Department of Dermatology, Royal North Shore Hospital, St Leonards, Sydney, Australia
| | - S D Smith
- Department of Dermatology, Royal North Shore Hospital, St Leonards, Sydney, Australia.,Northern Clinical School, Sydney Medical School, University of Sydney, Sydney, Australia.,The Dermatology and Skin Cancer Centre, Gosford and St Leonards, Sydney, Australia
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Ji J, Petropavlovskaia M, Khatchadourian A, Patapas J, Makhlin J, Rosenberg L, Maysinger D. Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in β-cells. J Cell Mol Med 2019; 23:2890-2900. [PMID: 30710421 PMCID: PMC6433726 DOI: 10.1111/jcmm.14172] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/14/2018] [Accepted: 12/29/2018] [Indexed: 01/05/2023] Open
Abstract
Both type 2 diabetes (T2D) and obesity are characterized by excessive hyperlipidaemia and subsequent lipid droplet (LD) accumulation in adipose tissue. To investigate whether LDs also accumulate in β-cells of T2D patients, we assessed the expression of PLIN2, a LD-associated protein, in non-diabetic (ND) and T2D pancreata. We observed an up-regulation of PLIN2 mRNA and protein in β-cells of T2D patients, along with significant changes in the expression of lipid metabolism, apoptosis and oxidative stress genes. The increased LD buildup in T2D β-cells was accompanied by inhibition of nuclear translocation of TFEB, a master regulator of autophagy and by down-regulation of lysosomal biomarker LAMP2. To investigate whether LD accumulation and autophagy were influenced by diabetic conditions, we used rat INS-1 cells to model the effects of hyperglycaemia and hyperlipidaemia on autophagy and metabolic gene expression. Consistent with human tissue, both LD formation and PLIN2 expression were enhanced in INS-1 cells under hyperglycaemia, whereas TFEB activation and autophagy gene expression were significantly reduced. Collectively, these results suggest that lipid clearance and overall homeostasis is markedly disrupted in β-cells under hyperglycaemic conditions and interventions ameliorating lipid clearance could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity.
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Affiliation(s)
- Jeff Ji
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | | | - Armen Khatchadourian
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
| | - Jason Patapas
- Department of Surgery, McGill University, Montreal, QC, Canada
| | - Julia Makhlin
- Department of Surgery, McGill University, Montreal, QC, Canada
| | | | - Dusica Maysinger
- Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
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Liang H, Nie J, Van Skike CE, Valentine JM, Orr ME. Mammalian Target of Rapamycin at the Crossroad Between Alzheimer's Disease and Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1128:185-225. [PMID: 31062331 DOI: 10.1007/978-981-13-3540-2_10] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Accumulating evidence suggests that Alzheimer's disease may manifest as a metabolic disorder with pathology and/or dysfunction in numerous tissues. Adults with Alzheimer's disease suffer with significantly more comorbidities than demographically matched Medicare beneficiaries (Zhao et al, BMC Health Serv Res 8:108, 2008b). Reciprocally, comorbid health conditions increase the risk of developing Alzheimer's disease (Haaksma et al, PLoS One 12(5):e0177044, 2017). Type 2 diabetes mellitus is especially notable as the disease shares many overlapping pathologies observed in patients with Alzheimer's disease, including hyperglycemia, hyperinsulinemia, insulin resistance, glucose intolerance, dyslipidemia, inflammation, and cognitive dysfunction, as described in Chap. 8 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al, Neurology 53(9):1937-1942, 1999; Voisin et al, Rev Med Interne 24(Suppl 3):288s-291s, 2003; Janson et al. Diabetes 53(2):474-481, 2004; Ristow M, J Mol Med (Berl) 82(8):510-529, 2004; Whitmer et al, BMJ 330(7504):1360, 2005, Curr Alzheimer Res 4(2):103-109, 2007; Ohara et al, Neurology 77(12):1126-1134, 2011). Although nondiabetic older adults also experience age-related cognitive decline, diabetes is uniquely associated with a twofold increased risk of Alzheimer's disease, as described in Chap. 2 of this book (Yoshitake et al, Neurology 45(6):1161-1168, 1995; Leibson et al, Am J Epidemiol 145(4):301-308, 1997; Ott et al. Neurology 53(9):1937-1942, 1999; Ohara et al, Neurology 77(12):1126-1134, 2011). Good glycemic control has been shown to improve cognitive status (Cukierman-et al, Diabetes Care 32(2):221-226, 2009), and the use of insulin sensitizers is correlated with a lower rate of cognitive decline in older adults (Morris JK, Burns JM, Curr Neurol Neurosci Rep 12(5):520-527, 2012). At the molecular level, the mechanistic/mammalian target of rapamycin (mTOR) plays a key role in maintaining energy homeostasis. Nutrient availability and cellular stress information, both extracellular and intracellular, are integrated and transduced through mTOR signaling pathways. Aberrant regulation of mTOR occurs in the brains of patients with Alzheimer's disease and in numerous tissues of individuals with type 2 diabetes (Mannaa et al, J Mol Med (Berl) 91(10):1167-1175, 2013). Moreover, modulating mTOR activity with a pharmacological inhibitor, rapamycin, provides wide-ranging health benefits, including healthy life span extension in numerous model organisms (Vellai et al, Nature 426(6967):620, 2003; Jia et al, Development 131(16):3897-3906, 2004; Kapahi et al, Curr Biol 14(10):885-890, 2004; Kaeberlein et al, Science 310(5751):1193-1196, 2005; Powers et al, Genes Dev 20(2):174-184, 2006; Harrison et al, Nature 460(7253):392-395, 2009; Selman et al, Science 326(5949):140-144, 2009; Sharp ZD, Strong R, J Gerontol A Biol Sci Med Sci 65(6):580-589, 2010), which underscores its importance to overall organismal health and longevity. In this chapter, we discuss the physiological role of mTOR signaling and the consequences of mTOR dysregulation in the brain and peripheral tissues, with emphasis on its relevance to the development of Alzheimer's disease and link to type 2 diabetes.
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Affiliation(s)
- Hanyu Liang
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jia Nie
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Candice E Van Skike
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Joseph M Valentine
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Miranda E Orr
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
- San Antonio Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, USA.
- Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, San Antonio, TX, USA.
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42
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Attenuation of Free Fatty Acid-Induced Muscle Insulin Resistance by Rosemary Extract. Nutrients 2018; 10:nu10111623. [PMID: 30400151 PMCID: PMC6267446 DOI: 10.3390/nu10111623] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 10/24/2018] [Accepted: 10/29/2018] [Indexed: 12/13/2022] Open
Abstract
Elevated blood free fatty acids (FFAs), as seen in obesity, impair muscle insulin action leading to insulin resistance and Type 2 diabetes mellitus. Serine phosphorylation of the insulin receptor substrate (IRS) is linked to insulin resistance and a number of serine/threonine kinases including JNK, mTOR and p70 S6K have been implicated in this process. Activation of the energy sensor AMP-activated protein kinase (AMPK) increases muscle glucose uptake, and in recent years AMPK has been viewed as an important target to counteract insulin resistance. We reported recently that rosemary extract (RE) increased muscle cell glucose uptake and activated AMPK. However, the effect of RE on FFA-induced muscle insulin resistance has never been examined. In the current study, we investigated the effect of RE in palmitate-induced insulin resistant L6 myotubes. Exposure of myotubes to palmitate reduced the insulin-stimulated glucose uptake, increased serine phosphorylation of IRS-1, and decreased the insulin-stimulated phosphorylation of Akt. Importantly, exposure to RE abolished these effects and the insulin-stimulated glucose uptake was restored. Treatment with palmitate increased the phosphorylation/activation of JNK, mTOR and p70 S6K whereas RE completely abolished these effects. RE increased the phosphorylation of AMPK even in the presence of palmitate. Our data indicate that rosemary extract has the potential to counteract the palmitate-induced muscle cell insulin resistance and further studies are required to explore its antidiabetic properties.
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Bifari F, Manfrini R, Dei Cas M, Berra C, Siano M, Zuin M, Paroni R, Folli F. Multiple target tissue effects of GLP-1 analogues on non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Pharmacol Res 2018; 137:219-229. [PMID: 30359962 DOI: 10.1016/j.phrs.2018.09.025] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2018] [Revised: 09/11/2018] [Accepted: 09/24/2018] [Indexed: 12/12/2022]
Abstract
Accumulating experimental and clinical evidences over the last decade indicate that GLP-1 analogues have a series of central nervous system and peripheral target tissues actions which are able to significantly influence the liver metabolism. GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction. While the experimental and clinical data are robust, the precise mechanisms of action potentially involved in these protective multi-target effects need further investigation. Here we present a systematic review of the most recent literature data on the multi-target effects of GLP-1 analogues on the liver, on adipose and muscular tissue and on the nervous system, all capable of influencing significant aspects of the fatty liver disease physiopathology. From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.
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Affiliation(s)
- Francesco Bifari
- Laboratory of Cell Metabolism and Regenerative Medicine, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Roberto Manfrini
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Michele Dei Cas
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Cesare Berra
- Metabolic Disease and Diabetes, Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Matteo Siano
- Department of Internal Medicine ASST Santi Paolo e Carlo, Milan, Italy
| | - Massimo Zuin
- Unit of Medicine, Gastroenterology and Hepatology, Milan, Italy
| | - Rita Paroni
- Laboratory of Clinical Biochemistry and Mass Spectrometry, Department of Health Science, University of Milan, Milan, Italy
| | - Franco Folli
- Unit of Endocrinology and Metabolism ASST Santi Paolo e Carlo, Department of Health Science, University of Milan, Milan, Italy.
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Stanhope KL, Goran MI, Bosy-Westphal A, King JC, Schmidt LA, Schwarz JM, Stice E, Sylvetsky AC, Turnbaugh PJ, Bray GA, Gardner CD, Havel PJ, Malik V, Mason AE, Ravussin E, Rosenbaum M, Welsh JA, Allister-Price C, Sigala DM, Greenwood MRC, Astrup A, Krauss RM. Pathways and mechanisms linking dietary components to cardiometabolic disease: thinking beyond calories. Obes Rev 2018; 19:1205-1235. [PMID: 29761610 PMCID: PMC6530989 DOI: 10.1111/obr.12699] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/09/2018] [Accepted: 03/31/2018] [Indexed: 12/11/2022]
Abstract
Calories from any food have the potential to increase risk for obesity and cardiometabolic disease because all calories can directly contribute to positive energy balance and fat gain. However, various dietary components or patterns may promote obesity and cardiometabolic disease by additional mechanisms that are not mediated solely by caloric content. Researchers explored this topic at the 2017 CrossFit Foundation Academic Conference 'Diet and Cardiometabolic Health - Beyond Calories', and this paper summarizes the presentations and follow-up discussions. Regarding the health effects of dietary fat, sugar and non-nutritive sweeteners, it is concluded that food-specific saturated fatty acids and sugar-sweetened beverages promote cardiometabolic diseases by mechanisms that are additional to their contribution of calories to positive energy balance and that aspartame does not promote weight gain. The challenges involved in conducting and interpreting clinical nutritional research, which preclude more extensive conclusions, are detailed. Emerging research is presented exploring the possibility that responses to certain dietary components/patterns are influenced by the metabolic status, developmental period or genotype of the individual; by the responsiveness of brain regions associated with reward to food cues; or by the microbiome. More research regarding these potential 'beyond calories' mechanisms may lead to new strategies for attenuating the obesity crisis.
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Affiliation(s)
- K L Stanhope
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - M I Goran
- Department of Preventive Medicine, Diabetes and Obesity Research Institute, University of Southern California, Los Angeles, CA, USA
| | - A Bosy-Westphal
- Institute of Human Nutrition and Food Science, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
| | - J C King
- Children's Hospital Oakland Research Institute, Oakland, CA, USA
| | - L A Schmidt
- Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, San Francisco, CA, USA
- California Clinical and Translational Science Institute, University of California, San Francisco, San Francisco, CA, USA
- Department of Anthropology, History, and Social Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - J-M Schwarz
- Touro University, Vallejo, CA, USA
- Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - E Stice
- Oregon Research Institute, Eugene, OR, USA
| | - A C Sylvetsky
- Department of Exercise and Nutrition Sciences, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - P J Turnbaugh
- Department of Microbiology and Immunology, G.W. Hooper Research Foundation, University of California, San Francisco, San Francisco, CA, USA
| | - G A Bray
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - C D Gardner
- Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - P J Havel
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
- Department of Nutrition, University of California, Davis, Davis, CA, USA
| | - V Malik
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - A E Mason
- Department of Psychiatry, Osher Center for Integrative Medicine, University of California, San Francisco, San Francisco, CA, USA
| | - E Ravussin
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - M Rosenbaum
- Division of Molecular Genetics, Department of Pediatrics, Columbia University, New York, NY, USA
| | - J A Welsh
- Department of Pediatrics, Emory University School of Medicine, Wellness Department, Children's Healthcare of Atlanta, Nutrition and Health Sciences Doctoral Program, Laney Graduate School, Emory University, Atlanta, GA, USA
| | - C Allister-Price
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - D M Sigala
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
| | - M R C Greenwood
- Department of Nutrition, University of California, Davis, Davis, CA, USA
| | - A Astrup
- Department of Nutrition, Exercise, and Sports, Faculty of Sciences, University of Copenhagen, Copenhagen, Denmark
| | - R M Krauss
- Children's Hospital Oakland Research Institute, Oakland, CA, USA
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Prevalence of type 2 diabetes mellitus among patients with hidradenitis suppurativa in the United States. J Am Acad Dermatol 2018; 79:71-76. [PMID: 29339240 DOI: 10.1016/j.jaad.2018.01.014] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Revised: 01/02/2018] [Accepted: 01/03/2018] [Indexed: 12/31/2022]
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46
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mTOR Inhibitor Therapy and Metabolic Consequences: Where Do We Stand? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2640342. [PMID: 30034573 PMCID: PMC6035806 DOI: 10.1155/2018/2640342] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 05/26/2018] [Indexed: 12/16/2022]
Abstract
mTOR (mechanistic target of rapamycin) protein kinase acts as a central integrator of nutrient signaling pathways. Besides the immunosuppressive role after solid organ transplantations or in the treatment of some cancers, another promising role of mTOR inhibitor as an antiaging therapeutic has emerged in the recent years. Acute or intermittent rapamycin treatment has some resemblance to calorie restriction in metabolic effects such as an increased insulin sensitivity. However, the chronic inhibition of mTOR by macrolide rapamycin or other rapalogs has been associated with glucose intolerance and insulin resistance and may even provoke type II diabetes. These metabolic adverse effects limit the use of mTOR inhibitors. Metformin is a widely used drug for the treatment of type 2 diabetes which activates AMP-activated protein kinase (AMPK), acting as calorie restriction mimetic. In addition to the glucose-lowering effect resulting from the decreased hepatic glucose production and increased glucose utilization, metformin induces fatty acid oxidations. Here, we review the recent advances in our understanding of the metabolic consequences regarding glucose metabolism induced by mTOR inhibitors and compare them to the metabolic profile provoked by metformin use. We further suggest metformin use concurrent with rapalogs in order to pharmacologically address the impaired glucose metabolism and prevent the development of new-onset diabetes mellitus after solid organ transplantations induced by the chronic rapalog treatment.
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González-Mariscal I, Montoro RA, Doyle ME, Liu QR, Rouse M, O'Connell JF, Santa-Cruz Calvo S, Krzysik-Walker SM, Ghosh S, Carlson OD, Lehrmann E, Zhang Y, Becker KG, Chia CW, Ghosh P, Egan JM. Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets. Diabetologia 2018; 61:1470-1483. [PMID: 29497784 PMCID: PMC6201315 DOI: 10.1007/s00125-018-4576-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 01/25/2018] [Indexed: 01/04/2023]
Abstract
AIMS/HYPOTHESIS The cannabinoid 1 receptor (CB1R) regulates insulin sensitivity and glucose metabolism in peripheral tissues. CB1R is expressed on pancreatic beta cells and is coupled to the G protein Gαi, suggesting a negative regulation of endogenous signalling in the beta cell. Deciphering the exact function of CB1R in beta cells has been confounded by the expression of this receptor on multiple tissues involved in regulating metabolism. Thus, in models of global genetic or pharmacological CB1R blockade, it is difficult to distinguish the indirect effects of improved insulin sensitivity in peripheral tissues from the direct effects of inhibiting CB1R in beta cells per se. To assess the direct contribution of beta cell CB1R to metabolism, we designed a mouse model that allows us to determine the role of CB1R specifically in beta cells in the context of whole-body metabolism. METHODS We generated a beta cell specific Cnr1 (CB1R) knockout mouse (β-CB1R-/-) to study the long-term consequences of CB1R ablation on beta cell function in adult mice. We measured beta cell function, proliferation and viability in these mice in response to a high-fat/high-sugar diet and induction of acute insulin resistance with the insulin receptor antagonist S961. RESULTS β-CB1R-/- mice had increased fasting (153 ± 23% increase at 10 weeks of age) and stimulated insulin secretion and increased intra-islet cAMP levels (217 ± 33% increase at 10 weeks of age), resulting in primary hyperinsulinaemia, as well as increased beta cell viability, proliferation and islet area (1.9-fold increase at 10 weeks of age). Hyperinsulinaemia led to insulin resistance, which was aggravated by a high-fat/high-sugar diet and weight gain, although beta cells maintained their insulin secretory capacity in response to glucose. Strikingly, islets from β-CB1R-/- mice were protected from diet-induced inflammation. Mechanistically, we show that this is a consequence of curtailment of oxidative stress and reduced activation of the NLRP3 inflammasome in beta cells. CONCLUSIONS/INTERPRETATION Our data demonstrate CB1R to be a negative regulator of beta cell function and a mediator of islet inflammation under conditions of metabolic stress. Our findings point to beta cell CB1R as a therapeutic target, and broaden its potential to include anti-inflammatory effects in both major forms of diabetes. DATA AVAILABILITY Microarray data have been deposited at GEO (GSE102027).
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Affiliation(s)
- Isabel González-Mariscal
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Rodrigo A Montoro
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Máire E Doyle
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Qing-Rong Liu
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Michael Rouse
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Jennifer F O'Connell
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Sara Santa-Cruz Calvo
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Susan M Krzysik-Walker
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Soumita Ghosh
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Olga D Carlson
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Elin Lehrmann
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Yongqing Zhang
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Kevin G Becker
- Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Chee W Chia
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Paritosh Ghosh
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA
| | - Josephine M Egan
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.
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Liu S, Li X, Wu Y, Duan R, Zhang J, Du F, Zhang Q, Li Y, Li N. Effects of vaspin on pancreatic β cell secretion via PI3K/Akt and NF-κB signaling pathways. PLoS One 2017; 12:e0189722. [PMID: 29240812 PMCID: PMC5730172 DOI: 10.1371/journal.pone.0189722] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 11/30/2017] [Indexed: 01/11/2023] Open
Abstract
Vaspin (visceral adipose tissue-derived serine protease inhibitor) is a recently discovered adipokine that has been implicated in diabetes mellitus and other metabolic disorders. However, the effects of vaspin on pancreatic β cell function and related mechanisms are not fully understood. Thus, the present study was performed to investigate the effects of vaspin on pancreatic β cell function and the potential underlying mechanisms. Both in vitro (rat insulinoma cells, INS-1) and in vivo (high fat diet fed rats) experiments were conducted. The results showed that vaspin significantly increased INS-1 cell secretory function. Potential mechanisms were explored using inhibitors, western blot and real-time PCR techniques. We found that vaspin increased the levels of IRS-2 mRNA and IRS-2 total protein, while decreased the serine phosphorylation level of IRS-2 protein. Moreover, vaspin increased the Akt phosphorylation protein level which was reversed by PI3K inhibitor ly294002. In addition, vaspin increased the phosphorylation levels of mTOR and p70S6K, which was inhibited by rapamycin. Meanwhile, we found that the NF-κB mRNA and protein levels were reduced after vaspin treatment, similar to the effect of NF-κB inhibitor TPCK. Furthermore, vaspin increased the glucose stimulated insulin secretion (GSIS) level, lowered blood glucose level and improved the glucose tolerance and insulin sensitivity of high fat diet fed rats. Hyperglycemic clamp test manifested that vaspin improved islet β cell function. Together, these findings provide a new understanding of the function of vaspin on pancreatic β cell and suggest that it may serve as a potential agent for the prevention and treatment of type 2 diabetes.
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Affiliation(s)
- Shiwei Liu
- Department of Endocrinology, Shanxi DAYI Hospital, Shanxi Medical University, Taiyuan, China
- Central Laboratory, Taiyuan Central Hospital, Shanxi Medical University, Taiyuan, China
- * E-mail:
| | - Xin Li
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Yaru Wu
- Central Laboratory, Taiyuan Central Hospital, Shanxi Medical University, Taiyuan, China
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Ruixue Duan
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Jiaxin Zhang
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Fang Du
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Qi Zhang
- Graduate School of Shanxi Medical University, Taiyuan, China
| | - Yuanbin Li
- Department of Endocrinology, Taiyuan Central Hospital, Shanxi Medical University, Taiyuan, China
| | - Naishi Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Dietary arginine affects the insulin signaling pathway, glucose metabolism and lipogenesis in juvenile blunt snout bream Megalobrama amblycephala. Sci Rep 2017; 7:7864. [PMID: 28801592 PMCID: PMC5554147 DOI: 10.1038/s41598-017-06104-3] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 06/07/2017] [Indexed: 12/19/2022] Open
Abstract
This study evaluated the mechanisms governing insulin resistance, glucose metabolism and lipogenesis in juvenile fish fed with graded levels of dietary arginine. The results showed that, compared with the control group (0.87%), 2.31% dietary arginine level resulted in the upregulation of the relative gene expression of IRS-1, PI3K and Akt in the insulin signaling pathway, while 2.70% dietary arginine level led to inhibition of these genes. 1.62% dietary arginine level upregulated glycolysis by increasing GK mRNA level; 2.70% dietary arginine level upregulated gluconeogenesis and resulted in high plasma glucose content by increasing PEPCK and G6P mRNA level. Furthermore, 2.70% dietary arginine level significantly lowered GLUT2 and increased PK mRNA levels. 1.62% dietary arginine level significantly upregulated ACC, FAS and G6PDH mRNA levels in the fat synthesis pathway and resulted in high plasma TG content. These results indicate that 1.62% dietary arginine level improves glycolysis and fatty acid synthesis in juvenile blunt snout bream. However, 2.70% dietary arginine level results in high plasma glucose, which could lead to negative feedback of insulin resistance, including inhibition of IRS-1 mRNA levels and activation of gluconeogenesis-related gene expression. This mechanism seems to be different from mammals at the molecular level.
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Chronic dietary exposure to branched chain amino acids impairs glucose disposal in vegans but not in omnivores. Eur J Clin Nutr 2017; 71:594-601. [PMID: 28145418 DOI: 10.1038/ejcn.2016.274] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Revised: 12/02/2016] [Accepted: 12/16/2016] [Indexed: 12/18/2022]
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