|
1
|
Oo TT. Repurposing metformin: A potential off-label indication for ischaemic stroke? Diabetes Obes Metab 2025; 27:1065-1078. [PMID: 39604047 DOI: 10.1111/dom.16105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/15/2024] [Accepted: 11/17/2024] [Indexed: 11/29/2024]
Abstract
The term 'clinical cemetery' is frequently used to characterize ischaemic stroke, one of the leading causes of mortality and long-term morbidity globally. Over the past two decades, a number of novel therapies have been investigated for ischaemic stroke. However, aside from mechanical thrombectomy, the only FDA-approved prescription for treating ischaemic stroke is tissue plasminogen activator, which has a limited therapeutic period. Although post-stroke rehabilitation therapies are helpful in improving functional recovery, their benefits cannot be yielded promptly. Nowadays, drug repurposing might be an appealing approach to expanding therapeutic options for ischaemic stroke. During the last decade, metformin has been extensively researched as a potential repurposing medicine for ischaemic stroke, with a focus on both preventive and therapeutic approaches. With regard to the idea of repurposing metformin in ischaemic stroke, this review aims to compile the available data from pre-clinical and clinical trials, address and clarify any discrepancies, and offer solutions.
Collapse
Affiliation(s)
- Thura Tun Oo
- Department of Biomedical Sciences, University of Illinois at Chicago, College of Medicine Rockford, Rockford, Illinois, USA
| |
Collapse
|
|
2
|
Loos JA, Negro PS, Ortega HH, Salinas FJ, Arán M, Pellizza L, Salerno GL, Cumino AC. Anti-echinococcal effect of metformin in advanced experimental cystic echinococcosis: reprogrammed intermediary carbon metabolism in the parasite. Antimicrob Agents Chemother 2024; 68:e0094124. [PMID: 39264188 PMCID: PMC11459915 DOI: 10.1128/aac.00941-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/09/2024] [Indexed: 09/13/2024] Open
Abstract
Metformin, a safe biguanide derivative with antiproliferative properties, has shown antiparasitic efficacy against the Echinococcus larval stage. Hence, we assessed the efficacy of a dose of 250 mg kg-1 day-1 in experimental models of advanced CE, at 6 and 12 months post-infection with oral and intraperitoneal administration, respectively. At this high dose, metformin reached intracystic concentrations between 0.7 and 1.7 mM and triggered Eg-TOR inhibition through AMPK activation by AMP-independent and -dependent mechanisms, which are dependent on drug dose. Cystic metformin uptake was controlled by increased expression of organic cation transporters in the presence of the drug. In both experimental models, metformin reduced the weight of parasite cysts, altered the ultrastructural integrity of their germinal layers, and reduced the intracystic availability of glucose, limiting the cellular carbon and energy charge and the proliferative capacity of metacestodes. This glucose depletion in the parasite was associated with a slight increase in cystic uptake of 2-deoxiglucose and the transcriptional induction of GLUT genes in metacestodes. In this context, drastic glycogen consumption led to increased lactate production and altered intermediary metabolism in treated metacestodes. Specifically, the fraction of reducing soluble sugars decreased twofold, and the levels of non-reducing soluble sugars, such as sucrose and trehalose, were modified in both cystic fluid and germinal cells. Taken together, our findings highlight the relevance of metformin as a promising candidate for CE treatment and warrant further research to improve the therapeutic conditions of this chronic zoonosis in humans.
Collapse
Affiliation(s)
- Julia A. Loos
- IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina
| | - Perla S. Negro
- Parasitología y Enfermedades Parasitarias, Facultad de Ciencias Veterinarias, Universidad Nacional de Rosario, Casilda, Santa Fe, Argentina
| | - Hugo H. Ortega
- Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina
| | - Facundo J. Salinas
- Centro de Medicina Comparada, ICiVet-Litoral, Universidad Nacional del Litoral-CONICET, Esperanza, Santa Fe, Argentina
| | - Martín Arán
- Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)—CONICET, Buenos Aires, Argentina
| | - Leonardo Pellizza
- Fundación Instituto Leloir e Instituto de Investigaciones Bioquímicas de Buenos Aires (IIBBA)—CONICET, Buenos Aires, Argentina
| | - Graciela L. Salerno
- Fundación Para Investigaciones Biológicas Aplicadas (FIBA), Mar del Plata, Argentina
| | - Andrea C. Cumino
- IIPROSAM, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Mar del Plata, Argentina
- Departamento de Química, Facultad de Ciencias Exactas y Naturales, Universidad Nacional de Mar del Plata (UNMdP), Mar del Plata, Argentina
| |
Collapse
|
|
3
|
Wang W, Chen S, Jiang Y, Ji J, Cong R. Expression of the C-allele of intronic rs8192675 in SLC2A2 is associated with improved glucose response to metformin. Genet Mol Biol 2024; 47:e20230281. [PMID: 39535164 PMCID: PMC11559485 DOI: 10.1590/1678-4685-gmb-2023-0281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 05/30/2024] [Indexed: 11/16/2024] Open
Abstract
Glucose is a critical nutrient for energy metabolism. The SLC2A2 gene is essential for glucose sensing and homeostasis, as it encodes the facilitated glucose transporter GLUT2. During diabetes treatment, the C-allele of rs8192675 in SLC2A2 has been found to regulate the action of metformin and reduce the absolute level of HbA1c more effectively than the T-allele. In this study, stable HEK293T cell lines carrying the CC, CT, and TT genotypes of rs8192675 in SLC2A2 were generated using CRISPR/Cas9-mediated genome editing. GLUT2 mRNA and protein levels were elevated in cell clones with the TC genotype compared to those with the CC genotype but were reduced relative to the TT genotype. Additionally, high concentrations of glucose or fructose induced more GLUT2 protein production in CT-genotype cells than that induced in CC-genotype cells, yet less than that induced in TT-genotype cells. Metformin induced a greater increase in GLUT2 expression and a smaller increase in activated AMPK protein expression in CC-genotype cells than those induced in TT-genotype cells, resulting in a remarkable reduction in activated mTOR and S6 levels. This study directly supports the biological mechanism linking the C-allele of rs8192675 with improved treatment outcomes in metformin therapy for diabetes.
Collapse
Affiliation(s)
- Wanjun Wang
- Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, School of Medicine, Tongji University, Shanghai, China
| | - Suying Chen
- Affiliated Hospital 2 of Nantong University, Department of Radiology, No.666 Shengli Road, Nantong, Jiangsu Province, China
| | - Yilei Jiang
- Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, School of Medicine, Tongji University, Shanghai, China
| | - Jianhong Ji
- Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Intensive Care Unit, Nantong, People's Republic of China
| | - Ruochen Cong
- Affiliated Hospital 2 of Nantong University, Department of Radiology, No.666 Shengli Road, Nantong, Jiangsu Province, China
| |
Collapse
|
|
4
|
Trotta RJ, Swanson KC, Klotz JL, Harmon DL. Influence of postruminal casein infusion and exogenous glucagon-like peptide 2 administration on the jejunal mucosal transcriptome in cattle. PLoS One 2024; 19:e0308983. [PMID: 39146343 PMCID: PMC11326568 DOI: 10.1371/journal.pone.0308983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Accepted: 08/03/2024] [Indexed: 08/17/2024] Open
Abstract
We previously demonstrated that postruminal casein infusion and exogenous glucagon-like peptide 2 (GLP-2) administration independently stimulated growth and carbohydrase activity of the pancreas and jejunal mucosa in cattle. The objective of the current study was to profile the jejunal mucosal transcriptome of cattle using next-generation RNA sequencing in response to postruminal casein infusion and exogenous GLP-2. Twenty-four Holstein steers [250 ± 23.1 kg body weight (BW)] received a continuous abomasal infusion of 3.94 g raw corn starch/kg of BW combined with either 0 or 1.30 g casein/kg of BW for 7 d. Steers received subcutaneous injections at 0800 and 2000 h to provide either 0 or 100 μg GLP-2/kg of BW per day. At the end of the 7-d treatment period, steers were slaughtered for collection of the jejunal mucosa. Total RNA was extracted from jejunal mucosal tissue, strand-specific cDNA libraries were prepared, and RNA sequencing was conducted to generate 150-bp paired-end reads at a depth of 40 M reads per sample. Differentially expressed genes (DEG), KEGG pathway enrichment, and gene ontology enrichment were determined based on the FDR-corrected P-value (padj). Exogenous GLP-2 administration upregulated (padj < 0.05) 667 genes and downregulated 1,101 genes of the jejunal mucosa. Sphingolipid metabolism, bile secretion, adherens junction, and galactose metabolism were among the top KEGG pathways enriched with upregulated DEG (padj < 0.05) in response to exogenous GLP-2 administration. The top gene ontologies enriched with upregulated DEG (padj < 0.05) in response to exogenous GLP-2 administration included nutrient metabolic processes, brush border and bicellular tight junction assembly, and enzyme and transporter activities. Exogenous GLP-2 administration increased or tended to increase (padj < 0.10) brush border carbohydrase (MGAM, LCT, TREH), hexose transporter (SLC5A1, SLC2A2), and associated transcription factor (HNF1, GATA4, KAT2B) mRNA expression of the jejunal mucosa. Gene ontologies and KEGG pathways that were downregulated (padj < 0.05) in response to exogenous GLP-2 were related to genetic information processing. Postruminal casein infusion downregulated (padj < 0.05) 7 jejunal mucosal genes that collectively did not result in enriched KEGG pathways or gene ontologies. This study highlights some of the transcriptional mechanisms associated with increased growth, starch assimilation capacity, and barrier function of the jejunal mucosa in response to exogenous GLP-2 administration.
Collapse
Affiliation(s)
- Ronald J. Trotta
- Department of Animal and Food Sciences, University of Kentucky, Lexington, Kentucky, United States of America
| | - Kendall C. Swanson
- Department of Animal Science, North Dakota State University, Fargo, North Dakota, United States of America
| | - James L. Klotz
- Forage-Animal Production Research Unit, United States Department of Agriculture, Agricultural Research Service, Lexington, Kentucky, United States of America
| | - David L. Harmon
- Department of Animal and Food Sciences, University of Kentucky, Lexington, Kentucky, United States of America
| |
Collapse
|
|
5
|
Ontawong A, Pengnet S, Thim-Uam A, Vaddhanaphuti CS, Munkong N, Phatsara M, Kuntakhut K, Inchai J, Amornlerdpison D, Rattanaphot T. Red rice bran aqueous extract ameliorate diabetic status by inhibiting intestinal glucose transport in high fat diet/STZ-induced diabetic rats. J Tradit Complement Med 2024; 14:391-402. [PMID: 39035687 PMCID: PMC11259718 DOI: 10.1016/j.jtcme.2023.12.003] [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: 07/21/2023] [Revised: 11/14/2023] [Accepted: 12/24/2023] [Indexed: 07/23/2024] Open
Abstract
Red rice (Oryza sativa L.) consumption has grown recently, partly due to its potential health benefits in several disease prevention. The impact of red rice bran aqueous extract (RRBE) on intestinal glucose uptake and diabetes mellitus (DM) progression has not been thoroughly investigated. This study aimed to evaluate the effect of RRBE on ex vivo intestinal glucose absorption and its potential as an antihyperglycemic compound using a high-fat diet and streptozotocin (STZ)-induced diabetic rats. High-fat diet/STZ-induced diabetic rats were supplemented with either 1000 mg/kg body weight (BW) of RRBE, 70 mg/kg BW of metformin (Met), or a combination of RRBE and Met for 3 months. Plasma parameters, intestinal glucose transport, morphology, liver and soleus muscle glycogen accumulation were assessed. Treatment with RRBE, metformin, or combination markedly reversed hyperglycemia, hypertriglyceridemia, insulin resistance, and pancreatic morphology changes associated with T2DM. Correspondingly, all supplements effectively downregulated glucose transporters, resulting in a reduction of intestinal glucose transport-additionally, liver and soleus muscle glycogen accumulation was reduced in RRBE + Met treated group. Taken together, RRBE potentially suppressed intestinal glucose transporters' function and expression, reducing diabetic status.
Collapse
Affiliation(s)
- Atcharaporn Ontawong
- Division of Physiology, School of Medical Sciences, University of Phayao, 19 Moo 2 Mae-Ka District, Muang, Phayao, 56000, Thailand
| | - Sirinat Pengnet
- Division of Physiology, School of Medical Sciences, University of Phayao, 19 Moo 2 Mae-Ka District, Muang, Phayao, 56000, Thailand
| | - Arthid Thim-Uam
- Division of Biochemistry, School of Medical Sciences, University of Phayao, 19 Moo 2 Mae-Ka District, Muang, Phayao, 56000, Thailand
| | - Chutima S. Vaddhanaphuti
- Faculty of Medicine, Chiang Mai University, 110 Faculty of Medicine, CMU, Inthawarorot Rd., Sri Phum, Muang, Chiang Mai, 50200, Thailand
| | - Narongsuk Munkong
- Department of Pathology, School of Medicine, University of Phayao, 19 Moo 2 Mae-Ka District, Muang, Phayao, 56000, Thailand
| | - Manussaborn Phatsara
- Department of Anatomy, Faculty of Medicine, Chiang Mai University, Chiang Mai, 52000, Thailand
| | - Kullanat Kuntakhut
- Center of Excellence in Agricultural Innovation for Graduate Entrepreneur, Maejo University, 63, Sansai-Phrao Street, Sansai, Chiang Mai, 50290, Thailand
| | - Jakkapong Inchai
- Faculty of Medicine, Chiang Mai University, 110 Faculty of Medicine, CMU, Inthawarorot Rd., Sri Phum, Muang, Chiang Mai, 50200, Thailand
| | - Doungporn Amornlerdpison
- Center of Excellence in Agricultural Innovation for Graduate Entrepreneur, Maejo University, 63, Sansai-Phrao Street, Sansai, Chiang Mai, 50290, Thailand
- Faculty of Fisheries Technology and Aquatic Resources, Maejo University, Chiang Mai, 50290, Thailand
| | - Teerawat Rattanaphot
- Center of Excellence in Agricultural Innovation for Graduate Entrepreneur, Maejo University, 63, Sansai-Phrao Street, Sansai, Chiang Mai, 50290, Thailand
| |
Collapse
|
|
6
|
Ke Z, Lu Z, Li Q, Tong W. Intestinal glucose excretion: A potential mechanism for glycemic control. Metabolism 2024; 152:155743. [PMID: 38007149 DOI: 10.1016/j.metabol.2023.155743] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 11/27/2023]
Abstract
The gut has been increasingly recognized in recent years as a pivotal organ in the maintenance of glucose homeostasis. Specifically, the profound and enduring improvement in glucose metabolism achieved through metabolic surgery to modify the anatomy of the gut has prompted scholars to acknowledge that the most effective strategy for treating type 2 diabetes mellitus (T2DM) involves the gut. The mechanisms underlying the regulation of glucose metabolism by the gut encompass gut hormones, bile acids, intestinal gluconeogenesis, gut microbiota, and signaling interactions between the gut and other organs (liver, brain, adipose, etc.). Recent studies have also revealed a novel phenomenon of glucose lowering through the gut: metabolic surgery and metformin promote the excretion of glucose from the circulation into the intestinal lumen by enterocytes. However, there is still limited understanding regarding the underlying mechanisms of intestinal glucose excretion and its contribution to glycemic control. This article reviews current research on intestinal glucose excretion while focusing on its role in T2DM management as well as potential mechanisms.
Collapse
Affiliation(s)
- Zhigang Ke
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Zongshi Lu
- Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, Chongqing Institute of Hypertension, Chongqing 400042, China
| | - Qing Li
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China
| | - Weidong Tong
- Department of General Surgery, Daping Hospital, Army Medical University, Chongqing 400042, China.
| |
Collapse
|
|
7
|
Ren Y, Tian Y, Hou M, Zhao Y, Li J, Aftab U, Rousseau X, Jiang R, Kang X, Tian Y, Gong Y. Evaluation of stimbiotic on growth performance and intestinal development of broilers fed corn- or wheat-based diets. Poult Sci 2023; 102:103094. [PMID: 37931376 PMCID: PMC10633449 DOI: 10.1016/j.psj.2023.103094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 08/30/2023] [Accepted: 09/05/2023] [Indexed: 11/08/2023] Open
Abstract
In the antibiotics-free era, stimbiotic (STB) has been suggested as a new alternative of antibiotic growth promoters to modulate intestinal health via stimulating dietary fiber utilization in poultry production. The aim of this study was to evaluate the effects of STB supplementation in corn- or wheat-basal diet on growth performance, intestinal development, and function of broilers. A total of 512 one-day-old Arbor Acres(AA)broilers were randomly allocated 4 treatments, including corn group (CG), corn + 100 g/t STB (CG + STB), wheat group (WG), wheat + 100 g/t STB (WG + STB). The broilers were weighed at the days of 14, 28, and 42, of which 8 repetitions per treatment were randomly selected to determine the intestinal morphology, intestinal barrier, and cecal microbiota and metabolites. Our data showed that STB increased (P < 0.05) feed intake, body weight and reduced FCR for the overall period (0-42 d). At 28 d of age, significant increases in villus height and the villus height-to-crypt depth ratio (V/C) were found in the STB supplementation groups (P < 0.05). Addition of STB significantly increased intestinal mucosal DAO and AMPK enzyme activity and the gene expression of OCLN, CLDN1, ZO1, MUC2, SGLT1, PEPT1, FABP2, Ghrelin, and GCG in jejunum (P < 0.05), and significantly decreased the expression of the PYY gene. In addition, STB increased the relative abundance of beneficial bacteria, such as Akkermansia, Bifidobacterium, and Oscillospirales (P < 0.05). A significant increase in cecal short-chain fatty acid (SCFAs) concentration was also observed in the STB supplementation groups. At the cellular level, STB cannot directly increase the expression of small intestinal epithelial cells, and may indirectly improve intestinal barrier function by increasing the level of sodium butyrate. Overall, these results indicated that STB supplementation could improve the growth performance, intestinal development and barrier functions, and fiber fermentation in cecum of broiler chickens.
Collapse
Affiliation(s)
- Yangguang Ren
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yixiang Tian
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang 453003, China
| | - Meng Hou
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yudian Zhao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Jing Li
- AB Vista, Marlborough SN8 4AN, UK
| | | | | | - Ruirui Jiang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Xiangtao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yadong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China
| | - Yujie Gong
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key Laboratory for Innovation and Utilization of Chicken Germplasm Resources, Zhengzhou 450046, China.
| |
Collapse
|
|
8
|
Wu Z, Xu C, Zheng T, Li Q, Yang S, Shao J, Guan W, Zhang S. A critical role of AMP-activated protein kinase in regulating intestinal nutrient absorption, barrier function, and intestinal diseases. J Cell Physiol 2022; 237:3705-3716. [PMID: 35892164 DOI: 10.1002/jcp.30841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 07/12/2022] [Accepted: 07/15/2022] [Indexed: 02/06/2023]
Abstract
As one of the most important organs in animals, the intestine is responsible for nutrient absorption and acts as a barrier between the body and the environment. Intestinal physiology and function require the participation of energy. 5'-adenosine monophosphate-activated protein kinase (AMPK), a classical and highly expressed energy regulator in intestinal cells, regulates the process of nutrient absorption and barrier function and is also involved in the therapy of intestinal diseases. Studies have yielded findings that AMPK regulates the absorption of glucose, amino acids, and fatty acids in the intestine primarily by regulating transportation systems, as we detailed here. Moreover, AMPK is involved in the regulation of the intestinal mechanical barrier and immune barrier through manipulating the expression of tight junctions, antimicrobial peptides, and secretory immunoglobulins. In addition, AMPK also participates in the regulation of intestinal diseases, which indicates that AMPK is a promising therapeutic target for intestinal diseases and cancer. In this review, we summarized the current understanding regarding how AMPK regulates intestinal nutrient absorption, barrier function, and intestinal diseases.
Collapse
Affiliation(s)
- Zhihui Wu
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Chengfei Xu
- School of Clinical Medicine, Chengdu Medical College, Chengdu, China
| | - Tenghui Zheng
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Qihui Li
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Siwang Yang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Jiayuan Shao
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China
| | - Wutai Guan
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China.,College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China
| | - Shihai Zhang
- Guangdong Province Key Laboratory of Animal Nutrition Control, College of Animal Science, South China Agricultural University, Guangzhou, China.,College of Animal Science and National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, South China Agricultural University, Guangzhou, China
| |
Collapse
|
|
9
|
Tang X, Xiong K. Epidermal growth factor activates EGFR/AMPK signalling to up-regulate the expression of SGLT1 and GLUT2 to promote intestinal glucose absorption in lipopolysaccharide challenged IPEC-J2 cells and piglets. ITALIAN JOURNAL OF ANIMAL SCIENCE 2022. [DOI: 10.1080/1828051x.2022.2073832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Xiaopeng Tang
- State Engineering Technology Institute for Karst Desertfication Control, School of Karst Science, Guizhou Normal University, Guiyang, China
| | - Kangning Xiong
- State Engineering Technology Institute for Karst Desertfication Control, School of Karst Science, Guizhou Normal University, Guiyang, China
| |
Collapse
|
|
10
|
Tang X, Xiong K. Intrauterine Growth Retardation Affects Intestinal Health of Suckling Piglets via Altering Intestinal Antioxidant Capacity, Glucose Uptake, Tight Junction, and Immune Responses. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2644205. [PMID: 35345830 PMCID: PMC8957421 DOI: 10.1155/2022/2644205] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 01/23/2022] [Accepted: 03/02/2022] [Indexed: 02/06/2023]
Abstract
The aim of the present study was to investigate the effects of intrauterine growth retardation (IUGR) on the intestinal morphology, intestinal epithelial cell apoptosis, intestinal antioxidant capacity, intestinal glucose absorption capacity, and intestinal barrier function of piglets during the suckling period. A total of eight normal-birth-weight (NBW) piglets and eight IUGR newborn piglets (Duroc × Landrace × Yorkshire) were selected from eight litters, one NBW and one IUGR newborn piglet per litter. In each litter, piglets with birth weight of 1.54 ± 0.04 kg (within one SD of the mean birth weight) were selected as NBW piglets and piglets with birth weight of 0.82 ± 0.03 kg (two SD below the mean birth weight) were selected as IUGR piglets. At 21 days of age, all piglets were killed by exsanguinations for sampling. The results showed the body weight (BW) of IUGR piglets on day 0, day 7, day 14, and day 21, and the body weight gain (BWG) of IUGR piglets was significantly lower than that of NBW piglets. IUGR piglets exhibited impaired intestinal morphology, raised enterocyte apoptosis, and increased oxidative damage. It showed that IUGR leads to a lower antioxidant capacity and glucose absorption in the jejunum. In accordance, IUGR caused the intestinal barrier dysfunction by impairing tight junctions and increasing intestinal inflammatory injury. Collectively, these results add to our understanding that IUGR affects intestinal health of suckling piglets via altering intestinal antioxidant capacity, glucose uptake, tight junction, and immune responses, and the slow growth of piglets with IUGR may be associated with intestinal injury.
Collapse
Affiliation(s)
- Xiaopeng Tang
- School of Karst Science, Guizhou Normal University, No. 116 North Baoshan Road, Yunyan District, Guiyang 550001, China
- State Engineering Technology Institute for Karst Desertification Control, No. 116 North Baoshan Road, Yunyan District, Guiyang 550001, China
| | - Kangning Xiong
- School of Karst Science, Guizhou Normal University, No. 116 North Baoshan Road, Yunyan District, Guiyang 550001, China
- State Engineering Technology Institute for Karst Desertification Control, No. 116 North Baoshan Road, Yunyan District, Guiyang 550001, China
| |
Collapse
|
|
11
|
Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis. Nat Commun 2022; 13:1135. [PMID: 35241650 PMCID: PMC8894485 DOI: 10.1038/s41467-022-28743-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/02/2022] [Indexed: 01/28/2023] Open
Abstract
The energy-dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5'-AMP-activated protein kinase, a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target in Type II diabetes. Despite its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Here we show that AMPKα1 deficiency in the intestine results in weight gain and impaired glucose tolerance under high fat diet feeding, while metformin administration fails to ameliorate these metabolic disorders in intestinal AMPKα1 knockout mice. Further, AMPKα1 in the intestine communicates with brown adipose tissue to promote thermogenesis. Mechanistically, we uncover a link between intestinal AMPKα1 activation and BAT thermogenic regulation through modulating anti-microbial peptide-controlled gut microbiota and the metabolites. Our findings identify AMPKα1-mediated mechanisms of intestine-BAT communication that may partially underlie the therapeutic effects of metformin.
Collapse
|
|
12
|
Li Y, Thelen KM, Fernández KM, Nelli R, Fardisi M, Rajput M, Trottier NL, Contreras GA, Moeser AJ. Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs. Am J Physiol Gastrointest Liver Physiol 2022; 322:G346-G359. [PMID: 34984921 PMCID: PMC9076411 DOI: 10.1152/ajpgi.00207.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by ∼ 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the β-adrenergic receptor (βAR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.
Collapse
Affiliation(s)
- Yihang Li
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Kyan M. Thelen
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Karina Matos Fernández
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Rahul Nelli
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Mahsa Fardisi
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Mrigendra Rajput
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Nathalie L. Trottier
- 3Department of Animal Science, Michigan State University, East Lansing, Michigan
| | - Genaro A. Contreras
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan
| | - Adam J. Moeser
- 1Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan,2Department of Physiology, Michigan State University, East Lansing, Michigan
| |
Collapse
|
|
13
|
|
|
14
|
Jayaprakasam VS, Paroder V, Schöder H. Variants and Pitfalls in PET/CT Imaging of Gastrointestinal Cancers. Semin Nucl Med 2021; 51:485-501. [PMID: 33965198 PMCID: PMC8338802 DOI: 10.1053/j.semnuclmed.2021.04.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the past two decades, PET/CT has become an essential modality in oncology increasingly used in the management of gastrointestinal (GI) cancers. Most PET/CT tracers used in clinical practice show some degree of GI uptake. This uptake is quite variable and knowledge of common patterns of biodistribution of various radiotracers is helpful in clinical practice. 18F-Fluoro-Deoxy-Glucose (FDG) is the most commonly used radiotracer and has quite a variable uptake within the bowel. 68Ga-Prostate specific membrane antigen (PSMA) shows intense uptake within the proximal small bowel loops. 11C-methyl-L-methionine (MET) shows high accumulation within the bowels, which makes it difficult to assess bowel or pelvic diseases. One must also be aware of technical artifacts causing difficulties in interpretations, such as high attenuation oral contrast material within the bowel lumen or misregistration artifact due to patient movements. It is imperative to know the common variants and benign diseases that can mimic malignant pathologies. Intense FDG uptake within the esophagus and stomach may be a normal variant or may be associated with benign conditions such as esophagitis, reflux disease, or gastritis. Metformin can cause diffuse intense uptake throughout the bowel loops. Intense physiologic uptake can also be seen within the anal canal. Segmental bowel uptake can be seen in inflammatory bowel disease, radiation, or medication induced enteritis/colitis or infection. Diagnosis of appendicitis or diverticular disease requires CT correlation, as normal appendix or diverticulum can show intense uptake. Certain malignant pathologies are known to have only low FDG uptake, such as early-stage esophageal adenocarcinoma, mucinous tumors, indolent lymphomas, and multicystic mesotheliomas. Response assessment, particularly in the neoadjuvant setting, can be limited by post-treatment inflammatory changes. Post-operative complications such as abscess or fistula formation can also show intense uptake and may obscure underlying malignant pathology. In the absence of clinical suspicion or rising tumor marker, the role of FDG PET/CT in routine surveillance of patients with GI malignancy is not clear.
Collapse
Affiliation(s)
- Vetri Sudar Jayaprakasam
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Viktoriya Paroder
- Body Imaging Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Heiko Schöder
- Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.
| |
Collapse
|
|
15
|
Ontawong A, Duangjai A, Srimaroeng C. Coffea arabica bean extract inhibits glucose transport and disaccharidase activity in Caco-2 cells. Biomed Rep 2021; 15:73. [PMID: 34405045 PMCID: PMC8329997 DOI: 10.3892/br.2021.1449] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 06/14/2021] [Indexed: 11/06/2022] Open
Abstract
The major constituents of Coffea arabica (coffee), including caffeine, chlorogenic acid and caffeic acid, exhibit antihyperglycemic properties in in vitro and in vivo models. However, whether Coffea arabica bean extract (CBE) regulates glucose uptake activity and the underlying mechanisms involved remain unclear. The aim of the present study was to examine the effects of CBE on glucose absorption and identify the mechanisms involved using an in vitro model. The uptake of a fluorescent glucose analog into Caco-2 colorectal adenocarcinoma cells was determined. The expression levels of sodium glucose co-transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) were evaluated. In addition, glycoside hydrolase enzyme activity was investigated. It was observed that CBE inhibited disaccharidase enzyme activity. Furthermore, CBE exerted an inhibitory effect on intestinal glucose absorption by downregulating SGLT1- and GLUT2-mediated 5' AMP-activated protein kinase phosphorylation and suppressing hepatocyte nuclear factor 1α expression. These data suggest that CBE may attenuate glucose absorption and may have potentially beneficial antihyperglycemic effects in the body; however, the mechanisms underlying the effects of CBE must be elucidated through further investigation.
Collapse
Affiliation(s)
- Atcharaporn Ontawong
- Division of Physiology, School of Medical Sciences, University of Phayao, Muang Phayao, Phayao 56000, Thailand
| | - Acharaporn Duangjai
- Division of Physiology, School of Medical Sciences, University of Phayao, Muang Phayao, Phayao 56000, Thailand
| | - Chutima Srimaroeng
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Nong Khai 52000, Thailand
| |
Collapse
|
|
16
|
YAP1 nuclear efflux and transcriptional reprograming follow membrane diminution upon VSV-G-induced cell fusion. Nat Commun 2021; 12:4502. [PMID: 34301937 PMCID: PMC8302681 DOI: 10.1038/s41467-021-24708-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Cells in many tissues, such as bone, muscle, and placenta, fuse into syncytia to acquire new functions and transcriptional programs. While it is known that fused cells are specialized, it is unclear whether cell-fusion itself contributes to programmatic-changes that generate the new cellular state. Here, we address this by employing a fusogen-mediated, cell-fusion system to create syncytia from undifferentiated cells. RNA-Seq analysis reveals VSV-G-induced cell fusion precedes transcriptional changes. To gain mechanistic insights, we measure the plasma membrane surface area after cell-fusion and observe it diminishes through increases in endocytosis. Consequently, glucose transporters internalize, and cytoplasmic glucose and ATP transiently decrease. This reduced energetic state activates AMPK, which inhibits YAP1, causing transcriptional-reprogramming and cell-cycle arrest. Impairing either endocytosis or AMPK activity prevents YAP1 inhibition and cell-cycle arrest after fusion. Together, these data demonstrate plasma membrane diminishment upon cell-fusion causes transient nutrient stress that may promote transcriptional-reprogramming independent from extrinsic cues.
Collapse
|
|
17
|
Moasses-Ghafari B, Fallahi B, Esfehani AF, Eftekhari M, Rahmani K, Eftekhari A, Geramifar P. Effect of Diet on Physiologic Bowel 18F-FDG Uptake. J Nucl Med Technol 2021; 49:241-245. [PMID: 34244224 DOI: 10.2967/jnmt.120.257857] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 03/26/2021] [Indexed: 12/30/2022] Open
Abstract
Intestinal 18F-FDG uptake is variable in whole-body PET/CT. In cancer patients, particularly those suspected of relapse or metastasis, 18F-FDG absorption might interfere with scan interpretation. This study evaluated the effect of diet on intestinal 18F-FDG absorption. Methods: In total, 214 patients referring for oncologic 18F-FDG PET/CT participated. They were randomly divided into 2 groups and asked to follow either a routine diet (RD) or a low-carbohydrate, high-fat diet (LCHFD) for 24 h before the study. The small bowel and different parts of the colon (the cecum; the ascending, transverse, and descending segments; and the hepatic and splenic flexures) were evaluated and visually interpreted by nuclear medicine experts. Bowel uptake was graded through comparison with that in the liver as absent, mild, moderate, or severe. Results: Significantly higher 18F-FDG uptake in the descending colon (P = 0.001) and small intestine (P = 0.01) was observed in the RD group than in the LCHFD group. After patients with bowel cancer were omitted from the statistical analysis, no significant differences in the final results were seen. Conclusion: An LCHFD for 24 h before 18F-FDG PET imaging resulted in lower 18F-FDG uptake in the descending colon and small bowel than did an RD, assisting the interpreting physician by reducing the intestinal activity interference for more accurate diagnostic interpretation.
Collapse
Affiliation(s)
| | - Babak Fallahi
- Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Armaghan Fard Esfehani
- Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Eftekhari
- Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Khaled Rahmani
- Social Determinants of Health Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; and
| | - Arash Eftekhari
- Diagnostic Radiology/Nuclear Medicine, Surrey Memorial Hospital and Jim Pattison Outpatient Care and Surgery Centre, Surrey, British Columbia, Canada
| | - Parham Geramifar
- Research Center for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran;
| |
Collapse
|
|
18
|
Ito J, Nogami M, Morita Y, Sakaguchi K, Komada H, Hirota Y, Sugawara K, Tamori Y, Zeng F, Murakami T, Ogawa W. Dose-dependent accumulation of glucose in the intestinal wall and lumen induced by metformin as revealed by 18 F-labelled fluorodeoxyglucose positron emission tomography-MRI. Diabetes Obes Metab 2021; 23:692-699. [PMID: 33236523 DOI: 10.1111/dom.14262] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/30/2020] [Accepted: 11/22/2020] [Indexed: 12/21/2022]
Abstract
AIM To investigate the relationships between various clinical variables and the metformin-induced accumulation of fluorodeoxyglucose (FDG) in the intestine, with distinction between the intestinal wall and lumen, in individuals with type 2 diabetes who were receiving metformin treatment and underwent 18 F-labelled FDG ([18 F]FDG) positron emission tomography (PET)-MRI. MATERIALS AND METHODS We evaluated intestinal accumulation of [18 F]FDG with both subjective (a five-point visual scale determined by two experienced radiologists) and objective analyses (measurement of the maximum standardized uptake value [SUVmax ]) in 26 individuals with type 2 diabetes who were receiving metformin and underwent [18 F]FDG PET-MRI. [18 F]FDG accumulation within the intestinal wall was discriminated from that in the lumen on the basis of SUVmax . RESULTS SUVmax for the large intestine was correlated with blood glucose level (BG) and metformin dose, but not with age, body mass index, HbA1c level or estimated glomerular filtration rate (eGFR). SUVmax for the small intestine was not correlated with any of these variables. Visual scale analysis yielded essentially similar results. Metformin dose and eGFR were correlated with SUVmax for the wall and lumen of the large intestine, whereas BG was correlated with that for the wall. Multivariable analysis identified metformin dose as an explanatory factor for SUVmax in the wall and lumen of the large intestine after adjustment for potential confounders including BG and eGFR. CONCLUSIONS Metformin dose is an independent determinant of [18 F]FDG accumulation in the wall and lumen of the large intestine in individuals treated with this drug.
Collapse
Affiliation(s)
- Jun Ito
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Munenobu Nogami
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasuko Morita
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazuhiko Sakaguchi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hisako Komada
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kenji Sugawara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshikazu Tamori
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- Division of Creative Health Promotion, Department of Social/Community Medicine and Health Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Feibi Zeng
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
19
|
Hinden L, Kogot-Levin A, Tam J, Leibowitz G. Pathogenesis of diabesity-induced kidney disease: role of kidney nutrient sensing. FEBS J 2021; 289:901-921. [PMID: 33630415 DOI: 10.1111/febs.15790] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/09/2021] [Accepted: 02/24/2021] [Indexed: 12/11/2022]
Abstract
Diabetes kidney disease (DKD) is a major healthcare problem associated with increased risk for developing end-stage kidney disease and high mortality. It is widely accepted that DKD is primarily a glomerular disease. Recent findings however suggest that kidney proximal tubule cells (KPTCs) may play a central role in the pathophysiology of DKD. In diabetes and obesity, KPTCs are exposed to nutrient overload, including glucose, free-fatty acids and amino acids, which dysregulate nutrient and energy sensing by mechanistic target of rapamycin complex 1 and AMP-activated protein kinase, with subsequent induction of tubular injury, inflammation, and fibrosis. Pharmacological treatments that modulate nutrient sensing and signaling in KPTCs, including cannabinoid-1 receptor antagonists and sodium glucose transporter 2 inhibitors, exert robust kidney protective effects. Shedding light on how nutrients are sensed and metabolized in KPTCs and in other kidney domains, and on their effects on signal transduction pathways that mediate kidney injury, is important for understanding the pathophysiology of DKD and for the development of novel therapeutic approaches in DKD and probably also in other forms of kidney disease.
Collapse
Affiliation(s)
- Liad Hinden
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Aviram Kogot-Levin
- Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory, Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel
| | - Gil Leibowitz
- Diabetes Unit and Endocrine Service, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| |
Collapse
|
|
20
|
Yakah W, Singh P, Brown J, Stoll B, Burrin D, Premkumar MH, Otu HH, Gu X, Dillon ST, Libermann TA, Freedman SD, Martin CR. Parenteral lipid emulsions induce unique ileal fatty acid and metabolomic profiles but do not increase the risk of necrotizing enterocolitis in preterm pigs. Am J Physiol Gastrointest Liver Physiol 2021; 320:G227-G239. [PMID: 33236951 PMCID: PMC7948117 DOI: 10.1152/ajpgi.00311.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood and distal ileum tissue were collected for fatty acid analysis. The distal ileum underwent histologic, proteomic, and metabolomic analyses. Eight pigs [3/14 SO (21%), 3/14 MO15 (21%), and 2/14 FO100 (14%)] developed NEC. No differences in NEC risk were evident between groups despite differences in induced fatty acid profiles in blood and ileal tissue. Metabolomic analysis of NEC versus no NEC tissue revealed differences in tryptophan metabolism and arachidonic acid-containing glycerophospholipids. Proteomic analysis demonstrated no differences by lipid group; however, 15 proteins differentiated NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling. Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC development. Metabolomic and proteomic analyses of NEC versus no NEC intestinal tissue provide mechanistic insights into the pathogenesis of NEC in preterm infants.NEW & NOTEWORTHY Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC risk in preterm pigs. Metabolomic and proteomic analyses provide mechanistic insights into NEC pathogenesis. Compared with healthy ileal tissue, metabolites in tryptophan metabolism and arachidonic acid-containing glycerophospholipids are increased in NEC tissue. Proteomic analysis differentiates NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling.
Collapse
Affiliation(s)
- William Yakah
- 1Department of Neonatology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Pratibha Singh
- 2Division of Gastroenterology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Joanne Brown
- 2Division of Gastroenterology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Barbara Stoll
- 3United States Department of Agriculture-Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Doug Burrin
- 3United States Department of Agriculture-Agricultural Research Service, Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Muralidhar H. Premkumar
- 4Section of Neonatology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
| | - Hasan H. Otu
- 5Department of Electrical and Computer Engineering, University of Nebraska-Lincoln, Lincoln, Nebraska
| | - Xuesong Gu
- 6Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Simon T. Dillon
- 6Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Towia A. Libermann
- 6Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Steven D. Freedman
- 2Division of Gastroenterology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts,7Division of Translational Research Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Camilia R. Martin
- 1Department of Neonatology Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts,7Division of Translational Research Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
21
|
Yang M, Darwish T, Larraufie P, Rimmington D, Cimino I, Goldspink DA, Jenkins B, Koulman A, Brighton CA, Ma M, Lam BYH, Coll AP, O'Rahilly S, Reimann F, Gribble FM. Inhibition of mitochondrial function by metformin increases glucose uptake, glycolysis and GDF-15 release from intestinal cells. Sci Rep 2021; 11:2529. [PMID: 33510216 PMCID: PMC7843649 DOI: 10.1038/s41598-021-81349-7] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023] Open
Abstract
Even though metformin is widely used to treat type2 diabetes, reducing glycaemia and body weight, the mechanisms of action are still elusive. Recent studies have identified the gastrointestinal tract as an important site of action. Here we used intestinal organoids to explore the effects of metformin on intestinal cell physiology. Bulk RNA-sequencing analysis identified changes in hexose metabolism pathways, particularly glycolytic genes. Metformin increased expression of Slc2a1 (GLUT1), decreased expression of Slc2a2 (GLUT2) and Slc5a1 (SGLT1) whilst increasing GLUT-dependent glucose uptake and glycolytic rate as observed by live cell imaging of genetically encoded metabolite sensors and measurement of oxygen consumption and extracellular acidification rates. Metformin caused mitochondrial dysfunction and metformin's effects on 2D-cultures were phenocopied by treatment with rotenone and antimycin-A, including upregulation of GDF15 expression, previously linked to metformin dependent weight loss. Gene expression changes elicited by metformin were replicated in 3D apical-out organoids and distal small intestines of metformin treated mice. We conclude that metformin affects glucose uptake, glycolysis and GDF-15 secretion, likely downstream of the observed mitochondrial dysfunction. This may explain the effects of metformin on intestinal glucose utilisation and food balance.
Collapse
Affiliation(s)
- Ming Yang
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Tamana Darwish
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Pierre Larraufie
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Debra Rimmington
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Irene Cimino
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Deborah A Goldspink
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Benjamin Jenkins
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Albert Koulman
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Cheryl A Brighton
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Marcella Ma
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Brian Y H Lam
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Anthony P Coll
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Stephen O'Rahilly
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK
| | - Frank Reimann
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK.
| | - Fiona M Gribble
- MRC Metabolic Diseases Unit, Addenbrooke's Hospital, Wellcome Trust/MRC Institute of Metabolic Science (IMS), University of Cambridge, Hills Road, Cambridge, CB2 0QQ, UK.
| |
Collapse
|
|
22
|
Demaré S, Kothari A, Calcutt NA, Fernyhough P. Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system. Expert Rev Neurother 2020; 21:45-63. [PMID: 33161784 PMCID: PMC9482886 DOI: 10.1080/14737175.2021.1847645] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective. Areas covered: The authors review literature on metformin treatment in Parkinson’s disease, Huntington’s disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol. Expert opinion: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.
Collapse
Affiliation(s)
- Sarah Demaré
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
| | - Asha Kothari
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
| | - Nigel A Calcutt
- Department of Pathology, University of California San Diego , La Jolla, CA, USA
| | - Paul Fernyhough
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre , Winnipeg, MB, Canada.,Department of Pharmacology and Therapeutics, University of Manitoba , Winnipeg, MB, Canada
| |
Collapse
|
|
23
|
Zhao L, Xuan Z, Song W, Zhang S, Li Z, Song G, Zhu X, Xie H, Zheng S, Song P. A novel role for farnesoid X receptor in the bile acid-mediated intestinal glucose homeostasis. J Cell Mol Med 2020; 24:12848-12861. [PMID: 33029898 PMCID: PMC7686993 DOI: 10.1111/jcmm.15881] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 08/27/2020] [Indexed: 12/14/2022] Open
Abstract
The farnesoid X receptor (FXR), as a bile acid (BA) sensor, plays an important role in the regulation of lipid metabolism. However, the effects and underlying molecular mechanisms of FXR on intestinal glucose homeostasis remain elusive. Herein, we demonstrated that FXR and glucose transporter 2 (GLUT2) are essential for BA‐mediated glucose homeostasis in the intestine. BA‐activated FXR enhanced glucose uptake in intestinal epithelial cells by increasing the expression of GLUT2, which depended on ERK1/2 phosphorylation via S1PR2. However, it also reduced the cell energy generation via inhibition of oxidative phosphorylation, which is crucial for intestinal glucose transport. Moreover, BA‐activated FXR signalling potently inhibited specific glucose flux through the intestinal epithelium to the circulation, which reduced the increase in blood glucose levels in mice following oral glucose administration. This trend was supported by the changed ratio of GLUT2 to SGLT1 in the brush border membrane (BBM), including especially decreased GLUT2 abundance in the BBM. Furthermore, impaired intestinal FXR signalling was observed in the patients with intestinal bile acid deficiency (IBAD). These findings uncover a novel function by which FXR sustains the intestinal glucose homeostasis and provide a rationale for FXR agonists in the treatment of IBAD‐related hyperglycaemia.
Collapse
Affiliation(s)
- Long Zhao
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Zefeng Xuan
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Wenfeng Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Shiyu Zhang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Zequn Li
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Guangyuan Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Xingxin Zhu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Haiyang Xie
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| | - Penghong Song
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,NHCPRC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, CAMS, Hangzhou, China.,Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.,Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases, Hangzhou, China
| |
Collapse
|
|
24
|
Koepsell H. Glucose transporters in the small intestine in health and disease. Pflugers Arch 2020; 472:1207-1248. [PMID: 32829466 PMCID: PMC7462918 DOI: 10.1007/s00424-020-02439-5] [Citation(s) in RCA: 158] [Impact Index Per Article: 31.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 07/11/2020] [Accepted: 07/17/2020] [Indexed: 12/23/2022]
Abstract
Absorption of monosaccharides is mainly mediated by Na+-D-glucose cotransporter SGLT1 and the facititative transporters GLUT2 and GLUT5. SGLT1 and GLUT2 are relevant for absorption of D-glucose and D-galactose while GLUT5 is relevant for D-fructose absorption. SGLT1 and GLUT5 are constantly localized in the brush border membrane (BBM) of enterocytes, whereas GLUT2 is localized in the basolateral membrane (BLM) or the BBM plus BLM at low and high luminal D-glucose concentrations, respectively. At high luminal D-glucose, the abundance SGLT1 in the BBM is increased. Hence, D-glucose absorption at low luminal glucose is mediated via SGLT1 in the BBM and GLUT2 in the BLM whereas high-capacity D-glucose absorption at high luminal glucose is mediated by SGLT1 plus GLUT2 in the BBM and GLUT2 in the BLM. The review describes functions and regulations of SGLT1, GLUT2, and GLUT5 in the small intestine including diurnal variations and carbohydrate-dependent regulations. Also, the roles of SGLT1 and GLUT2 for secretion of enterohormones are discussed. Furthermore, diseases are described that are caused by malfunctions of small intestinal monosaccharide transporters, such as glucose-galactose malabsorption, Fanconi syndrome, and fructose intolerance. Moreover, it is reported how diabetes, small intestinal inflammation, parental nutrition, bariatric surgery, and metformin treatment affect expression of monosaccharide transporters in the small intestine. Finally, food components that decrease D-glucose absorption and drugs in development that inhibit or downregulate SGLT1 in the small intestine are compiled. Models for regulations and combined functions of glucose transporters, and for interplay between D-fructose transport and metabolism, are discussed.
Collapse
Affiliation(s)
- Hermann Koepsell
- Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070, Würzburg, Germany.
| |
Collapse
|
|
25
|
Schreuder N, Klarenbeek H, Vendel BN, Jager PL, Kosterink JGW, van Puijenbroek EP. Discontinuation of metformin to prevent metformin-induced high colonic FDG uptake: is 48 h sufficient? Ann Nucl Med 2020; 34:833-839. [PMID: 32815120 PMCID: PMC7584522 DOI: 10.1007/s12149-020-01509-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/11/2020] [Indexed: 12/14/2022]
Abstract
Objective In this retrospective, single-center observational study, we investigated whether discontinuing metformin for at least 48 h prevents metformin-induced [18F]fluorodeoxyglucose (FDG) uptake in all segments of the colon. Methods Patients with type 2 diabetes who were using metformin before undergoing an FDG PET/CT scan were included. Two groups were created: patients who discontinued metformin for less than 48 h (< 48 h group) and patients who discontinued metformin for between 48 and 72 h (≥ 48 h group). A control group comprised non-diabetic patients who were not using metformin before undergoing an FDG PET/CT. We visually scored the uptake of FDG in four segments of the colon—the ascendens, transversum, descendens, and rectosigmoid—using a four-point scale (1–4) and considered scores of 3 or 4 to be clinically significant. Results Colonic FDG uptake in the ≥ 48 h group (n = 23) was higher than uptake in the control group (n = 96) in the colon descendens [odds ratio (OR) 14.0; 95% confidence interval (CI) 4.8–40.9; p value: 0.001] and rectosigmoid (OR 11.3; 95% CI 4.0–31.9; p value: 0.001), and there was no difference in the colon ascendens and transversum. Colonic FDG uptake in the < 48 h group (n = 25) was higher than uptake in the ≥ 48 h group (n = 23) in the colon transversum (OR 4.8; 95% CI 1.3–18.5; p value: 0.022) and rectosigmoid (p value: 0.023), and there was no difference in the colon ascendens and descendens. Conclusions Discontinuing metformin for 48 h before undergoing an FDG PET/CT still gives a high uptake in the distal parts of the colon when compared with non-diabetic patients who are not using metformin. Discontinuing metformin for 48 h seems to be useful for scanning the more proximal segments of the colon.
Collapse
Affiliation(s)
- Nanno Schreuder
- Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands.
- GE Healthcare Radiopharmacy Zwolle, Zwolle, The Netherlands.
| | - Hedwig Klarenbeek
- Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands
| | - Brian N Vendel
- Department of Nuclear Medicine, Isala Hospital, Zwolle, The Netherlands
| | - Pieter L Jager
- Department of Nuclear Medicine, Isala Hospital, Zwolle, The Netherlands
| | - Jos G W Kosterink
- Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands
- Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Eugène P van Puijenbroek
- Groningen Research Institute of Pharmacy, Pharmacotherapy, Epidemiology and Economics, University of Groningen, Antonius Deusinglaan 1, Groningen, The Netherlands
- Netherlands Pharmacovigilance Centre Lareb, 's Hertogenbosch, The Netherlands
| |
Collapse
|
|
26
|
Morita Y, Nogami M, Sakaguchi K, Okada Y, Hirota Y, Sugawara K, Tamori Y, Zeng F, Murakami T, Ogawa W. Enhanced Release of Glucose Into the Intraluminal Space of the Intestine Associated With Metformin Treatment as Revealed by [ 18F]Fluorodeoxyglucose PET-MRI. Diabetes Care 2020; 43:1796-1802. [PMID: 32493754 DOI: 10.2337/dc20-0093] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 04/06/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Positron emission tomography (PET)-computed tomography has revealed that metformin promotes the intestinal accumulation of [18F]fluorodeoxyglucose (FDG), a nonmetabolizable glucose derivative. It has remained unknown, however, whether this accumulation occurs in the wall or intraluminal space of the intestine. We here addressed this question with the use of [18F]FDG PET-MRI, a recently developed imaging method with increased accuracy of registration and high soft-tissue contrast. RESEARCH DESIGN AND METHODS Among 244 individuals with type 2 diabetes who underwent PET-MRI, we extracted 24 pairs of subjects matched for age, BMI, and HbA1c level who were receiving treatment with metformin (metformin group) or were not (control group). We evaluated accumulation of [18F]FDG in different portions of the intestine with both a visual scale and measurement of maximum standardized uptake value (SUVmax), and such accumulation within the intestinal wall or lumen was discriminated on the basis of SUVmax. RESULTS SUVmax of the jejunum, ileum, and right or left hemicolon was greater in the metformin group than in the control group. [18F]FDG accumulation in the ileum and right or left hemicolon, as assessed with the visual scale, was also greater in the metformin group. SUVmax for the intraluminal space of the ileum and right or left hemicolon, but not that for the intestinal wall, was greater in the metformin group than in the control group. CONCLUSIONS Metformin treatment was associated with increased accumulation of [18F]FDG in the intraluminal space of the intestine, suggesting that this drug promotes the transport of glucose from the circulation into stool.
Collapse
Affiliation(s)
- Yasuko Morita
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Munenobu Nogami
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazuhiko Sakaguchi
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuko Okada
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kenji Sugawara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshikazu Tamori
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Creative Health Promotion, Department of Social/Community Medicine and Health Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Feibi Zeng
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Takamichi Murakami
- Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
27
|
Phytochemicals and Gastrointestinal Cancer: Cellular Mechanisms and Effects to Change Cancer Progression. Biomolecules 2020; 10:biom10010105. [PMID: 31936288 PMCID: PMC7022462 DOI: 10.3390/biom10010105] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Revised: 12/21/2019] [Accepted: 12/23/2019] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal (GI) cancer is a prevailing global health disease with a high incidence rate which varies by region. It is a huge economic burden on health care providers. GI cancer affects different organs in the body such as the gastric organs, colon, esophagus, intestine, and pancreas. Internal and external factors like smoking, obesity, urbanization, genetic mutations, and prevalence of Helicobacter pylori and Hepatitis B and Hepatitis C viral infections could increase the risk of GI cancer. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in fruits, grains, and vegetables. Consumption of phytochemicals may protect against chronic diseases like cardiovascular disease, neurodegenerative disease, and cancer. Multiple studies have assessed the chemoprotective effect of selected phytochemicals in GI cancer, offering support to their potential towards reducing the pathogenesis of the disease. The aim of this review was to summarize the current knowledge addressing the anti-cancerous effects of selected dietary phytochemicals on GI cancer and their molecular activities on selected mechanisms, i.e., nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), detoxification enzymes, adenosine monophosphate activated protein kinase (AMPK), wingless-related integration site/β-catenin (wingless-related integration site (Wnt) β-catenin, cell apoptosis, phosphoinositide 3-kinases (PI3K)/ protein kinase B AKT/ mammalian target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK). In this review phytochemicals were classified into four main categories: (i) carotenoids, including lutein, lycopene, and β-carotene; (ii) proanthocyanidins, including quercetin and ellagic acid; (iii) organosulfur compounds, including allicin, allyl propyl disulphide, asparagusic acid, and sulforaphane; and (iv) other phytochemicals including pectin, curcumins, p-coumaric acid and ferulic acid. Overall, phytochemicals improve cancer prognosis through the downregulation of β-catenin phosphorylation, therefore enhancing apoptosis, and upregulation of the AMPK pathway, which supports cellular homeostasis. Nevertheless, more studies are needed to provide a better understanding of the mechanism of cancer treatment using phytochemicals and possible side effects associated with this approach.
Collapse
|
|
28
|
Dengler F, Gäbel G. The Fast Lane of Hypoxic Adaptation: Glucose Transport Is Modulated via A HIF-Hydroxylase-AMPK-Axis in Jejunum Epithelium. Int J Mol Sci 2019; 20:ijms20204993. [PMID: 31601024 PMCID: PMC6834319 DOI: 10.3390/ijms20204993] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 10/07/2019] [Accepted: 10/08/2019] [Indexed: 12/21/2022] Open
Abstract
The intestinal epithelium is able to adapt to varying blood flow and, thus, oxygen availability. Still, the adaptation fails under pathologic situations. A better understanding of the mechanisms underlying the epithelial adaptation to hypoxia could help to improve the therapeutic approach. We hypothesized that the short-term adaptation to hypoxia is mediated via AMP-activated protein kinase (AMPK) and that it is coupled to the long-term adaptation by a common regulation mechanism, the HIF-hydroxylase enzymes. Further, we hypothesized the transepithelial transport of glucose to be part of this short-term adaptation. We conducted Ussing chamber studies using isolated lagomorph jejunum epithelium and cell culture experiments with CaCo-2 cells. The epithelia and cells were incubated under 100% and 21% O2, respectively, with the panhydroxylase inhibitor dimethyloxalylglycine (DMOG) or under 1% O2. We showed an activation of AMPK under hypoxia and after incubation with DMOG by Western blot. This could be related to functional effects like an impairment of Na+-coupled glucose transport. Inhibitor studies revealed a recruitment of glucose transporter 1 under hypoxia, but not after incubation with DMOG. Summing up, we showed an influence of hydroxylase enzymes on AMPK activity and similarities between hypoxia and the effects of hydroxylase inhibition on functional changes.
Collapse
Affiliation(s)
- Franziska Dengler
- Institute of Veterinary Physiology, University of Leipzig, 04103 Leipzig, Germany.
| | - Gotthold Gäbel
- Institute of Veterinary Physiology, University of Leipzig, 04103 Leipzig, Germany.
| |
Collapse
|
|
29
|
Foretz M, Guigas B, Viollet B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat Rev Endocrinol 2019; 15:569-589. [PMID: 31439934 DOI: 10.1038/s41574-019-0242-2] [Citation(s) in RCA: 401] [Impact Index Per Article: 66.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/11/2019] [Indexed: 02/07/2023]
Abstract
Despite its position as the first-line drug for treatment of type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1-dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. In addition, the discovery that metformin inhibits the mitochondrial respiratory chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the centre of its proposed mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations in cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase 1 and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3-phosphate dehydrogenase have been proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissue-resident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide 1 and the intestinal bile acid pool and alterations in gut microbiota composition.
Collapse
Affiliation(s)
- Marc Foretz
- INSERM, U1016, Institut Cochin, Paris, France
- CNRS, UMR8104, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Centre, Leiden, Netherlands
| | - Benoit Viollet
- INSERM, U1016, Institut Cochin, Paris, France.
- CNRS, UMR8104, Paris, France.
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
| |
Collapse
|
|
30
|
King SJ, Bunz M, Chappell A, Scharl M, Docherty M, Jung B, Lytle C, McCole DF. AMPK mediates inhibition of electrolyte transport and NKCC1 activity by reactive oxygen species. Am J Physiol Gastrointest Liver Physiol 2019; 317:G171-G181. [PMID: 31070932 PMCID: PMC6734373 DOI: 10.1152/ajpgi.00317.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Reactive oxygen species such as H2O2 are believed to play a prominent role in the injury and loss of transport function that affect the intestinal epithelium in inflammatory conditions such as inflammatory bowel diseases. Defects in intestinal epithelial ion transport regulation contribute to dysbiosis and inflammatory phenotypes. We previously showed that H2O2 inhibits Ca2+-dependent Cl- secretion across intestinal epithelial cells (IECs) via a phosphatidylinositol 3-kinase (PI3K)- and extracellular signal-regulated kinase (ERK)-dependent mechanism that occurs, at least in part, through inhibition of the basolateral Na+-K+-2Cl- cotransporter NKCC1. NKCC1 governs Cl- entry into crypt IECs and thus plays a critical role in maintaining the driving force for Cl- secretion. Electrolyte transport consumes large amounts of cellular energy, and direct pharmacological activation of the cellular energy sensor AMP-activated protein kinase (AMPK) has been shown to inhibit a number of ion transport proteins. Here, we show that H2O2 activates AMPK in human IEC lines and ex vivo human colon. Moreover, we demonstrate that the inhibitory effect of H2O2 on Ca2+-dependent Cl- secretion and NKCC1 activity is AMPK-dependent. This inhibitory effect is associated with a physical interaction between AMPK and NKCC1, as well as increased phosphorylation (Thr212,217) of NKCC1, without causing NKCC1 internalization. These data identify a key role for AMPK-NKCC1 interaction as a point of convergence for suppression of colonic epithelial ion transport by inflammatory reactive oxygen species.NEW & NOTEWORTHY H2O2 inhibition of intestinal epithelial Ca2+-dependent Cl- secretion involves recruitment of AMP-activated protein kinase (AMPK) downstream of ERK and phosphatidylinositol 3-kinase signaling pathways, physical interaction of AMPK with the Na+-K+-2Cl- cotransporter NKCC1, and AMPK-dependent suppression of NKCC1-mediated electrolyte influx without causing NKCC1 internalization. It is intriguing that, in human intestinal epithelial cell lines and human colon, H2O2 activation of AMPK increased phosphorylation of NKCC1 residues required for promoting, not inhibiting, NKCC1 activity. These data identify an elevated complexity of AMPK regulation of NKCC1 in the setting of an inflammatory stimulus.
Collapse
Affiliation(s)
- Stephanie J. King
- 1Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Michael Bunz
- 2Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California,3Kreisklinik Woert an der Donau, Department of Anaesthesiology and Intensive Care Medicine, Woerth an der Donau, Germany
| | - Alfred Chappell
- 2Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California
| | - Michael Scharl
- 2Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California,4Division of Gastroenterology and Hepatology, Zurich Center for Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland
| | - Michael Docherty
- 2Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California
| | - Barbara Jung
- 2Division of Gastroenterology, School of Medicine, University of California, San Diego, La Jolla, California
| | - Christian Lytle
- 1Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| | - Declan F. McCole
- 1Division of Biomedical Sciences, University of California, Riverside, Riverside, California
| |
Collapse
|
|
31
|
AMPK-Mediated Regulation of Alpha-Arrestins and Protein Trafficking. Int J Mol Sci 2019; 20:ijms20030515. [PMID: 30691068 PMCID: PMC6387238 DOI: 10.3390/ijms20030515] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/17/2019] [Accepted: 01/17/2019] [Indexed: 12/18/2022] Open
Abstract
The adenosine monophosphate-activated protein kinase (AMPK) plays a central role in the regulation of cellular metabolism. Recent studies reveal a novel role for AMPK in the regulation of glucose and other carbohydrates flux by controlling the endocytosis of transporters. The first step in glucose metabolism is glucose uptake, a process mediated by members of the GLUT/SLC2A (glucose transporters) or HXT (hexose transporters) family of twelve-transmembrane domain glucose transporters in mammals and yeast, respectively. These proteins are conserved from yeast to humans, and multiple transporters—each with distinct kinetic properties—compete for plasma membrane occupancy in order to enhance or limit the rate of glucose uptake. During growth in the presence of alternative carbon sources, glucose transporters are removed and replaced with the appropriate transporter to help support growth in response to this environment. New insights into the regulated protein trafficking of these transporters reveal the requirement for specific α-arrestins, a little-studied class of protein trafficking adaptor. A defining feature of the α-arrestins is that each contains PY-motifs, which can bind to the ubiquitin ligases from the NEDD4/Rsp5 (Neural precursor cell Expressed, Developmentally Down-regulated 4 and Reverses Spt- Phenotype 5, respectively) family. Specific association of α-arrestins with glucose and carbohydrate transporters is thought to bring the ubiquitin ligase in close proximity to its membrane substrate, and thereby allows the membrane cargo to become ubiquitinated. This ubiquitination in turn serves as a mark to stimulate endocytosis. Recent results show that AMPK phosphorylation of the α-arrestins impacts their abundance and/or ability to stimulate carbohydrate transporter endocytosis. Indeed, AMPK or glucose limitation also controls α-arrestin gene expression, adding an additional layer of complexity to this regulation. Here, we review the recent studies that have expanded the role of AMPK in cellular metabolism to include regulation of α-arrestin-mediated trafficking of transporters and show that this mechanism of regulation is conserved over the ~150 million years of evolution that separate yeast from man.
Collapse
|
|
32
|
Intracellular signaling of the AMP-activated protein kinase. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2019; 116:171-207. [DOI: 10.1016/bs.apcsb.2018.12.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
|
|
33
|
AMP-Activated Protein Kinase (AMPK)-Dependent Regulation of Renal Transport. Int J Mol Sci 2018; 19:ijms19113481. [PMID: 30404151 PMCID: PMC6274953 DOI: 10.3390/ijms19113481] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 10/26/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
AMP-activated kinase (AMPK) is a serine/threonine kinase that is expressed in most cells and activated by a high cellular AMP/ATP ratio (indicating energy deficiency) or by Ca2+. In general, AMPK turns on energy-generating pathways (e.g., glucose uptake, glycolysis, fatty acid oxidation) and stops energy-consuming processes (e.g., lipogenesis, glycogenesis), thereby helping cells survive low energy states. The functional element of the kidney, the nephron, consists of the glomerulus, where the primary urine is filtered, and the proximal tubule, Henle's loop, the distal tubule, and the collecting duct. In the tubular system of the kidney, the composition of primary urine is modified by the reabsorption and secretion of ions and molecules to yield final excreted urine. The underlying membrane transport processes are mainly energy-consuming (active transport) and in some cases passive. Since active transport accounts for a large part of the cell's ATP demands, it is an important target for AMPK. Here, we review the AMPK-dependent regulation of membrane transport along nephron segments and discuss physiological and pathophysiological implications.
Collapse
|
|
34
|
Jaikumkao K, Pongchaidecha A, Chueakula N, Thongnak LO, Wanchai K, Chatsudthipong V, Chattipakorn N, Lungkaphin A. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, slows the progression of renal complications through the suppression of renal inflammation, endoplasmic reticulum stress and apoptosis in prediabetic rats. Diabetes Obes Metab 2018; 20:2617-2626. [PMID: 29923295 DOI: 10.1111/dom.13441] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 06/05/2018] [Accepted: 06/15/2018] [Indexed: 12/13/2022]
Abstract
AIM To evaluate the renoprotective roles of dapagliflozin in prediabetic rats in order to elucidate the effects of this sodium-glucose co-transporter-2 (SGLT2) inhibitor on the renal complications associated with metabolic dysfunction in diet-induced obesity. METHODS Obesity was induced by feeding a high-fat diet (HFD) to male Wistar rats for 16 weeks. HFD-fed rats were treated with dapagliflozin (1 mg/kg/d) or metformin (30 mg/kg/d) by oral gavage for 4 weeks after insulin resistance had been established. The metabolic characteristics and renal function associated with lipid accumulation, inflammation, fibrosis, endoplasmic reticulum (ER) stress and apoptosis in the renal tissue were examined. RESULTS The results showed that HFD-fed rats developed both obesity and impaired renal function, along with increased renal triglyceride accumulation. Importantly, dapagliflozin had greater efficacy in improving renal function and reducing both body weight and visceral fat accumulation than metformin treatment. Dapagliflozin and metformin were found to have similar effects regarding the suppression of renal triglycerides, superoxide dismutase (SOD) expression and malondialdehyde (MDA) levels, subsequently leading to a decrease in renal inflammation and fibrosis. Renal ER stress and apoptosis were increased in HFD-fed rats and were effectively reduced after administration of dapagliflozin. The expression of renal SGLT2 was not affected by administration of dapagliflozin or metformin. CONCLUSION Collectively, these findings indicate that dapagliflozin exerts renoprotective effects by alleviating obesity-induced renal inflammation, fibrosis, ER stress, apoptosis and lipid accumulation in the prediabetic condition.
Collapse
Affiliation(s)
- Krit Jaikumkao
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Anchalee Pongchaidecha
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nuttawud Chueakula
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - La-Ongdao Thongnak
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Keerati Wanchai
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
| | | | - Nipon Chattipakorn
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Research and Training Centre, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Anusorn Lungkaphin
- Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Centre for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai, Thailand
| |
Collapse
|
|
35
|
Uerlings J, Song ZG, Hu XY, Wang SK, Lin H, Buyse J, Everaert N. Heat exposure affects jejunal tight junction remodeling independently of adenosine monophosphate-activated protein kinase in 9-day-old broiler chicks. Poult Sci 2018; 97:3681-3690. [PMID: 29901744 DOI: 10.3382/ps/pey229] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 05/21/2018] [Indexed: 12/26/2022] Open
Abstract
Dysfunction of the intestinal epithelial barrier under elevated temperatures is assumed to prompt pathological conditions and to eventually impede chickens' growth, resulting in massive economic losses in broiler industries. The aims of this research were to determine the impact of acute heat stress on the intestinal tight junction network of broiler chicks (Gallus domesticus L.) and to elucidate whether adenosine monophosphate-activated protein kinase (AMPK) was involved in the integrated response of the broiler's gastrointestinal tract to heat stress. A total of 80 9-day-old Arbor Acres chicks were subjected to temperature treatment (thermoneutral versus heat stress) and AMPK inhibition treatment (5 mg/kg body weight intraperitoneal injection of compound C vs. sham treatment) for 72 h. In addition to monitoring growth performance, the mRNA and protein levels of key tight junction proteins, target components of the AMPK pathway, and biomarkers of intestinal inflammation and oxidative stress were assessed in the jejunum under both stressors at 24 and 72 h. An increase of the major tight junction proteins, claudin-1 and zonula occludens-1, was implemented in response to an exacerbated expression of the AMP-activated protein kinase. Heat stress did not affect zootechnical performance but was confirmed by an increased gene expression of heat shock proteins 70 and 90 as well as heat shock factor-1. In addition, hyperthermia induced significant effects on tight junction proteins, although it was independent of AMPK.
Collapse
Affiliation(s)
- J Uerlings
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong 271018, P. R. China.,Precision Livestock and Nutrition Unit, TERRA Teaching and Research Centre, University of Liege, Gembloux 5030, Belgium
| | - Z G Song
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong 271018, P. R. China
| | - X Y Hu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong 271018, P. R. China
| | - S K Wang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong 271018, P. R. China
| | - H Lin
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Taian, Shandong 271018, P. R. China
| | - Johan Buyse
- Laboratory of Livestock Physiology, Division of Animal and Human Health, KU Leuven, Heverlee 3001, Belgium
| | - N Everaert
- Precision Livestock and Nutrition Unit, TERRA Teaching and Research Centre, University of Liege, Gembloux 5030, Belgium
| |
Collapse
|
|
36
|
Transcriptomic analysis reveals effects of fucoxanthin on intestinal glucose transport. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.08.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
|
|
37
|
Lee SA, Whenham N, Bedford MR. Review on docosahexaenoic acid in poultry and swine nutrition: Consequence of enriched animal products on performance and health characteristics. ACTA ACUST UNITED AC 2018; 5:11-21. [PMID: 30899805 PMCID: PMC6406981 DOI: 10.1016/j.aninu.2018.09.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 08/23/2018] [Accepted: 09/04/2018] [Indexed: 12/21/2022]
Abstract
Omega-3 polyunsaturated fatty acids (n-3 PUFA) are linked to a variety of health benefits against human disorders and disease. However, the typical western diet is generally low in n-3 PUFA and high in n-6 PUFA, suggesting that the recommended intake of these essential fatty acids is seldom achieved. Therefore, dietary enrichment of animal meat and eggs with n-3 PUFA could help increase consumption of these fatty acids. Fish oils and microalgae (MA) are rich sources of long chain n-3 PUFA, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Feeding these marine products has been shown to increase DHA content of tissues and yolk, however, this may also lead to an increased requirement for anti-oxidants to prevent oxidative deterioration and associated negative sensory attributes. Nonetheless, increased DHA has been linked to promising results in animal growth, fertility, immunity and bone strength in both pigs and poultry. These findings suggest that feeding DHA-rich ingredients to mono-gastric can enrich human diets as well as providing additional benefits to the animal.
Collapse
|
|
38
|
Role of AMP-activated protein kinase in kidney tubular transport, metabolism, and disease. Curr Opin Nephrol Hypertens 2017; 26:375-383. [DOI: 10.1097/mnh.0000000000000349] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
|
|
39
|
Dengler F, Rackwitz R, Pfannkuche H, Gäbel G. Glucose transport across lagomorph jejunum epithelium is modulated by AMP-activated protein kinase under hypoxia. J Appl Physiol (1985) 2017; 123:1487-1500. [PMID: 28860168 DOI: 10.1152/japplphysiol.00436.2017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The gastrointestinal epithelium possesses adaptation mechanisms to cope with huge variations in blood flow and subsequently oxygenation. Since sufficient energy supply is crucial under hypoxic conditions, glucose uptake especially must be regulated by these adaptation mechanisms. Therefore, we investigated glucose transport under hypoxic conditions. Jejunal epithelia of rabbits were incubated in Ussing chambers under short-circuit current conditions. Hypoxia was simulated by gassing with 1% O2 instead of 100% O2. The activity of sodium-coupled glucose transporter-1 (SGLT-1) was assessed by measuring the increase of short circuit current ( Isc) after the addition of 2 mM glucose to the mucosal buffer solution. We observed decreased activity of SGLT-1 after hypoxia compared with control conditions. To investigate underlying mechanisms, epithelia were exposed to agonists and antagonists of AMP-activated protein kinase (AMPK) before assessment of SGLT-1-mediated transport and the pAMPK/AMPK protein ratio. Preincubation with the antagonist restored SGLT-1 activity under hypoxic conditions to the level of control conditions, indicating an involvement of AMPK in the downregulation of SGLT-1 activity under hypoxia, which was confirmed in Western blot analysis of pAMPK/AMPK. Transepithelial flux studies using radioactively labeled glucose, ortho-methyl-glucose, fructose, and mannitol revealed no changes after hypoxic incubation. Therefore, we could exclude a decreased transepithelial glucose transport rate and increased paracellular conductance under hypoxia. In conclusion, our study hints at a decreased activity of SGLT-1 under hypoxic conditions in an AMPK-dependent manner. However, transepithelial transport of glucose is maintained. Therefore, we suggest other transport mechanisms, especially glucose transporter 1 and/or 2 to substitute SGLT-1 under hypoxia. NEW & NOTEWORTHY To our knowledge, this is the first approach to simulate hypoxia and study its effects in the jejunal epithelium using the Ussing chamber technique. We were able show that AMPK plays a role in the downregulation of SGLT-1 and that there seems to be an upregulation of other glucose transport mechanisms in the apical membrane of lagomorph jejunum epithelium under hypoxia, securing the epithelial energy supply and thus integrity.
Collapse
Affiliation(s)
| | - Reiko Rackwitz
- Institute of Veterinary Physiology, University of Leipzig , Germany
| | - Helga Pfannkuche
- Institute of Veterinary Physiology, University of Leipzig , Germany
| | - Gotthold Gäbel
- Institute of Veterinary Physiology, University of Leipzig , Germany
| |
Collapse
|
|
40
|
Sun X, Zhu MJ. AMP-activated protein kinase: a therapeutic target in intestinal diseases. Open Biol 2017; 7:170104. [PMID: 28835570 PMCID: PMC5577448 DOI: 10.1098/rsob.170104] [Citation(s) in RCA: 46] [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: 05/03/2017] [Accepted: 07/25/2017] [Indexed: 02/07/2023] Open
Abstract
Adenosine monophosphate (AMP)-activated protein kinase (AMPK), a highly conserved energy sensor, has a crucial role in cardiovascular, neurodegenerative and inflammatory diseases, as well as in cancer and metabolic disorders. Accumulating studies have demonstrated that AMPK activation enhances paracellular junctions, nutrient transporters, autophagy and apoptosis, and suppresses inflammation and carcinogenesis in the intestine, indicating an essential role of AMPK in intestinal health. AMPK inactivation is an aetiological factor in intestinal dysfunctions. This review summarizes the favourable outcomes of AMPK activation on intestinal health, and discusses AMPK as a potential therapeutic target for intestinal diseases.
Collapse
Affiliation(s)
- Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA 99164, USA
- School of Food Science, University of Idaho, Moscow, ID 83844, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA 99164, USA
- School of Food Science, University of Idaho, Moscow, ID 83844, USA
| |
Collapse
|
|
41
|
Bhattacherjee A, Hrynets Y, Betti M. Transport of the Glucosamine-Derived Browning Product Fructosazine (Polyhydroxyalkylpyrazine) Across the Human Intestinal Caco-2 Cell Monolayer: Role of the Hexose Transporters. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:4642-4650. [PMID: 28535336 DOI: 10.1021/acs.jafc.7b01611] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
The transport mechanism of fructosazine, a glucosamine self-condensation product, was investigated using a Caco-2 cell model. Fructosazine transport was assessed by measuring the bidirectional permeability coefficient across Caco-2 cells. The mechanism of transport was evaluated using phlorizin, an inhibitor of sodium-dependent glucose cotransporters (SGLT) 1 and 2, phloretin and quercetin, inhibitors of glucose transporters (GLUT) 1 and 2, transcytosis inhibitor wortmannin, and gap junction disruptor cytochalasin D. The role of hexose transporters was further studied using downregulated or overexpressed cell lines. The apparent permeability (Pa,b) of fructosazine was 1.30 ± 0.02 × 10-6 cm/s. No significant (p > 0.05) effect was observed in fructosazine transport by adding wortmannin and cytochalasin D. The presence of phlorizin, phloretin, and quercetin decreased fructosazine transport. The downregulated GLUT cells line was unable to transport fructosazine. In human intestinal epithelial Caco-2 cells, GLUT1 or GLUT2 and SGLT are mainly responsible for fructosazine transport.
Collapse
Affiliation(s)
- Abhishek Bhattacherjee
- Department of Agricultural, Food and Nutritional Science, University of Alberta 410 Agriculture/Forestry Centre, Edmonton AB T6G 2P5, Canada
| | - Yuliya Hrynets
- Department of Agricultural, Food and Nutritional Science, University of Alberta 410 Agriculture/Forestry Centre, Edmonton AB T6G 2P5, Canada
| | - Mirko Betti
- Department of Agricultural, Food and Nutritional Science, University of Alberta 410 Agriculture/Forestry Centre, Edmonton AB T6G 2P5, Canada
| |
Collapse
|
|
42
|
Nyane NA, Tlaila TB, Malefane TG, Ndwandwe DE, Owira PMO. Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights. Eur J Pharmacol 2017; 803:103-111. [PMID: 28322845 DOI: 10.1016/j.ejphar.2017.03.042] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 03/16/2017] [Accepted: 03/17/2017] [Indexed: 12/25/2022]
Abstract
Metformin is a widely used drug for the treatment of type 2 diabetes (T2D). Its blood glucose-lowering effects are initially due to inhibition of hepatic glucose production and increased peripheral glucose utilization. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular complications in patients with diabetes. Adenosine Monophosphate Activated-Protein Kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Recent evidence shows that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profiles, blood pressure and insulin-resistance making it a novel therapeutic target in the treatment of T2D. Naringenin a flavonoid found in high concentrations as its glycone naringin in citrus fruits, has been reported to have antioxidant, antiatherogenic, anti- dyslipidemic and anti-diabetic effects. It has been shown that naringenin exerts its anti-diabetic effects by inhibition of gluconeogenesis through upregulations of AMPK hence metformin-like effects. Naringin has further been shown to have non-glycemic affects like metformin that mitigate inflammation and cell proliferation. This review evaluates the potential of naringenin as anti-diabetic, anti-dyslipidemic anti-inflammatory and antineoplastic agent similar to metformin and proposes its further development for therapeutic use in clinical practice.
Collapse
Affiliation(s)
- Ntsoaki Annah Nyane
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Thabiso Bethwel Tlaila
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Tanki Gabriel Malefane
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Dudu Edith Ndwandwe
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa
| | - Peter Mark Oroma Owira
- Molecular and Clinical Pharmacology Research Laboratory, Department of Pharmacology, Discipline of Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, P.O. Box X5401, Durban, South Africa.
| |
Collapse
|
|
43
|
Lakhani A, Khan SR, Bharwani N, Stewart V, Rockall AG, Khan S, Barwick TD. FDG PET/CT Pitfalls in Gynecologic and Genitourinary Oncologic Imaging. Radiographics 2017; 37:577-594. [DOI: 10.1148/rg.2017160059] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Affiliation(s)
- Amish Lakhani
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Sairah R. Khan
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Nishat Bharwani
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Victoria Stewart
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Andrea G. Rockall
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Sameer Khan
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| | - Tara D. Barwick
- From the Department of Radiology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, Fulham Palace Road, London W6 8RF, England (A.L., S.R.K., N.B., V.S., S.K., T.D.B.); Faculty of Medicine, Department of Surgery and Cancer (A.L., N.B., T.D.B.), and Department of Surgery and Cancer (A.G.R.), Imperial College London, London, England; and Department of Radiology, the Royal Marsden NHS Foundation Trust, London, England (A.G.R.)
| |
Collapse
|
|
44
|
Sun X, Yang Q, Rogers CJ, Du M, Zhu MJ. AMPK improves gut epithelial differentiation and barrier function via regulating Cdx2 expression. Cell Death Differ 2017; 24:819-831. [PMID: 28234358 PMCID: PMC5423107 DOI: 10.1038/cdd.2017.14] [Citation(s) in RCA: 176] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Revised: 01/09/2017] [Accepted: 01/19/2017] [Indexed: 12/16/2022] Open
Abstract
Impairment in gut epithelial integrity and barrier function is associated with many diseases. The homeostasis of intestinal barrier is based on a delicate regulation of epithelial proliferation and differentiation. AMP-activated protein kinase (AMPK) is a master regulator of energy metabolism, and cellular metabolites are intrinsically involved in epigenetic modifications governing cell differentiation. We aimed to evaluate the regulatory role of AMPK on intestinal epithelial development and barrier function. In this study, AMPK activator (AICAR) improved the barrier function of Caco-2 cells as indicated by increased transepithelial electrical resistance and reduced paracellular FITC-dextran permeability; consistently, AICAR enhanced epithelial differentiation and tight junction formation. Transfection of Caco-2 cells with AMPK WT plasmid, which enhances AMPK activity, improved epithelial barrier function and epithelial differentiation, while K45R (AMPK dominant negative mutant) impaired; these changes were correlated with the expression of caudal type homeobox 2 (CDX2), the key transcription factor committing cells to intestinal epithelial lineage. CDX2 deficiency abolished intestinal differentiation promoted by AMPK activation. Mechanistically, AMPK inactivation was associated with polycomb repressive complex 2 regulated enrichment of H3K27me3, the inhibitory histone modification, and lysine-specific histone demethylase-1-mediated reduction of H3K4me3, a permissive histone modification. Those histone modifications provide a mechanistic link between AMPK and CDX2 expression. Consistently, epithelial AMPK knockout in vivo reduced CDX2 expression, impaired intestinal barrier function, integrity and ultrastructure of tight junction, and epithelial cell migration, promoted intestinal proliferation and exaggerated dextran sulfate sodium-induced colitis. In summary, AMPK enhances intestinal barrier function and epithelial differentiation via promoting CDX2 expression, which is partially mediated by altered histone modifications in the Cdx2 promoter.
Collapse
Affiliation(s)
- Xiaofei Sun
- School of Food Science, Washington State University, Pullman 99164, WA, USA.,School of Food Science, University of Idaho, Moscow 83844, ID, USA
| | - Qiyuan Yang
- Department of Animal Science, Washington State University, Pullman 99164, WA, USA
| | - Carl J Rogers
- Department of Animal Science, Washington State University, Pullman 99164, WA, USA
| | - Min Du
- Department of Animal Science, Washington State University, Pullman 99164, WA, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman 99164, WA, USA.,School of Food Science, University of Idaho, Moscow 83844, ID, USA
| |
Collapse
|
|
45
|
Ma X, Jiang Z, Lai C. Significance of Increasing n-3 PUFA Content in Pork on Human Health. Crit Rev Food Sci Nutr 2017; 56:858-70. [PMID: 26237277 DOI: 10.1080/10408398.2013.850059] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Evidence for the health-promoting effects of food rich in n-3 polyunsaturated fatty acids (n-3 PUFA) is reviewed. Pork is an important meat source for humans. According to a report by the US Department of Agriculture ( http://www.ers.usda.gov/topics ), the pork consumption worldwide in 2011 was about 79.3 million tons, much higher than that of beef (48.2 million tons). Pork also contains high levels of unsaturated fatty acids relative to ruminant meats (Enser, M., Hallett, K., Hewett, B., Fursey, G. A. J. and Wood, J. D. (1996) . Fatty acid content and composition of English beef, lamb, and pork at retail. Meat Sci. 44:443-458). The available literature indicates that the levels of eicosatetraenoic and docosahexaenoic in pork may be increased by fish-derived or linseed products, the extent of which being dependent on the nature of the supplementation. Transgenic pigs and plants show promise with high content of n-3 PUFA and low ratio of n-6/n-3 fatty acids in their tissues. The approaches mentioned for decreasing n-6/n-3 ratios have both advantages and disadvantages. Selected articles are critically reviewed and summarized.
Collapse
Affiliation(s)
- Xianyong Ma
- a The Key Laboratory of Animal Nutrition and Feed Science (South China) of Ministry of Agriculture, State Key Laboratory of Livestock and Poultry Breeding, Institute of Animal Science, Guangdong Academy of Agricultural Sciences , Guangzhou , China
| | - Zongyong Jiang
- a The Key Laboratory of Animal Nutrition and Feed Science (South China) of Ministry of Agriculture, State Key Laboratory of Livestock and Poultry Breeding, Institute of Animal Science, Guangdong Academy of Agricultural Sciences , Guangzhou , China
| | - Chaoqiang Lai
- b Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University , Boston , Massachusetts , USA
| |
Collapse
|
|
46
|
Role of AMP-activated protein kinase α1 in angiotensin-II-induced renal Tgfß-activated kinase 1 activation. Biochem Biophys Res Commun 2016; 476:267-272. [DOI: 10.1016/j.bbrc.2016.05.111] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 05/22/2016] [Indexed: 01/12/2023]
|
|
47
|
López-Yoldi M, Castilla-Madrigal R, Lostao MP, Barber A, Prieto J, Martínez JA, Bustos M, Moreno-Aliaga MJ. Cardiotrophin-1 decreases intestinal sugar uptake in mice and in Caco-2 cells. Acta Physiol (Oxf) 2016; 217:217-26. [PMID: 26972986 DOI: 10.1111/apha.12674] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 10/12/2015] [Accepted: 03/04/2016] [Indexed: 12/15/2022]
Abstract
AIM Cardiotrophin-1 (CT-1) is a member of the IL-6 family of cytokines with a key role in glucose and lipid metabolism. In the current investigation, we examined the in vivo and in vitro effects of CT-1 treatment on intestinal sugar absorption in different experimental models. METHODS rCT-1 effects on α-Methyl-D-glucoside uptake were assessed in everted intestinal rings from wild-type and CT-1(-/-) mice and in Caco-2 cells. rCT-1 actions on SGLT-1 expression in brush border membrane vesicles and the identification of the potential signalling pathways involved were determined by Western blot. RESULTS In vivo administration (0.2 mg kg(-1) ) of rCT-1 caused a significant decrease on α-Methyl-D-glucoside uptake in everted intestinal rings from wild-type and CT-1(-/-) mice after short-term and long-term treatments. Similarly, in vitro treatment (1-50 ng mL(-1) ) with rCT-1 reduced α-Methyl-D-glucoside uptake in everted intestinal rings. In Caco-2 cells, rCT-1 treatment (20 ng mL(-1) , 1 and 24 h) lowered apical uptake of α-Methyl-D-glucoside in parallel with a decrease on SGLT-1 protein expression. rCT-1 promoted the phosphorylation of STAT-3 after 5 and 15 min treatment, but inhibited the activation by phosphorylation of AMPK after 30 and 60 min. Interestingly, pre-treatment with the JAK/STAT inhibitor (AG490) and with the AMPK activator (AICAR) reversed the inhibitory effects of rCT-1 on α-Methyl-D-glucoside uptake. AICAR also prevented the inhibition of SGLT-1 observed in rCT-1-treated cells. CONCLUSIONS CT-1 inhibits intestinal sugar absorption by the reduction of SGLT-1 levels through the AMPK pathway, which could also contribute to explain the hypoglycaemic and anti-obesity properties of CT-1.
Collapse
Affiliation(s)
- M. López-Yoldi
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
- Centre for Nutrition Research; University of Navarra; Pamplona Navarra Spain
| | - R. Castilla-Madrigal
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
- Centre for Nutrition Research; University of Navarra; Pamplona Navarra Spain
| | - M. P. Lostao
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
- Centre for Nutrition Research; University of Navarra; Pamplona Navarra Spain
- IdiSNA; Navarra Institute for Health Research; Pamplona Spain
| | - A. Barber
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
| | - J. Prieto
- Department of Gene Therapy and Hepatology; CIMA; University of Navarra; Pamplona Navarra Spain
- CIBERehd; Institute of Health Carlos III; Madrid Spain
| | - J. A. Martínez
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
- Centre for Nutrition Research; University of Navarra; Pamplona Navarra Spain
- IdiSNA; Navarra Institute for Health Research; Pamplona Spain
- CIBERobn; Physiopathology of Obesity and Nutrition; Institute of Health Carlos III; Madrid Spain
| | - M. Bustos
- Department of Gene Therapy and Hepatology; CIMA; University of Navarra; Pamplona Navarra Spain
| | - M. J. Moreno-Aliaga
- Department of Nutrition, Food Science and Physiology; University of Navarra; Pamplona Navarra Spain
- Centre for Nutrition Research; University of Navarra; Pamplona Navarra Spain
- IdiSNA; Navarra Institute for Health Research; Pamplona Spain
- CIBERobn; Physiopathology of Obesity and Nutrition; Institute of Health Carlos III; Madrid Spain
| |
Collapse
|
|
48
|
Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets 2016; 20:1109-25. [PMID: 26998950 DOI: 10.1517/14728222.2016.1168808] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Glycemic control is important in diabetes mellitus to minimize the progression of the disease and the risk of potentially devastating complications. Inhibition of the sodium-glucose cotransporter SGLT2 induces glucosuria and has been established as a new anti-hyperglycemic strategy. SGLT1 plays a distinct and complementing role to SGLT2 in glucose homeostasis and, therefore, SGLT1 inhibition may also have therapeutic potential. AREAS COVERED This review focuses on the physiology of SGLT1 in the small intestine and kidney and its pathophysiological role in diabetes. The therapeutic potential of SGLT1 inhibition, alone as well as in combination with SGLT2 inhibition, for anti-hyperglycemic therapy are discussed. Additionally, this review considers the effects on other SGLT1-expressing organs like the heart. EXPERT OPINION SGLT1 inhibition improves glucose homeostasis by reducing dietary glucose absorption in the intestine and by increasing the release of gastrointestinal incretins like glucagon-like peptide-1. SGLT1 inhibition has a small glucosuric effect in the normal kidney and this effect is increased in diabetes and during inhibition of SGLT2, which deliver more glucose to SGLT1 in late proximal tubule. In short-term studies, inhibition of SGLT1 and combined SGLT1/SGLT2 inhibition appeared to be safe. More data is needed on long-term safety and cardiovascular consequences of SGLT1 inhibition.
Collapse
Affiliation(s)
- Panai Song
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,c Department of Nephrology, Second Xiangya Hospital , Central South University , Changsha , China
| | - Akira Onishi
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,d Division of Nephrology, Department of Medicine , Jichi Medical University , Shimotsuke , Japan
| | - Hermann Koepsell
- e Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute , University of Würzburg , Würzburg , Germany
| | - Volker Vallon
- a Division of Nephrology & Hypertension, Department of Medicine , University of California San Diego , La Jolla , CA , USA.,b VA San Diego Healthcare System , San Diego , CA , USA.,f Department of Pharmacology , University of California San Diego , La Jolla , CA , USA
| |
Collapse
|
|
49
|
Abstract
Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.
Collapse
Affiliation(s)
- Laura J McCreight
- Pearson Group, Division of Cardiovascular and Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Mailbox 12, Level 5, Dundee, DD1 9SY, UK
| | - Clifford J Bailey
- School of Life and Health Sciences, Aston University, Birmingham, UK
| | - Ewan R Pearson
- Pearson Group, Division of Cardiovascular and Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Mailbox 12, Level 5, Dundee, DD1 9SY, UK.
| |
Collapse
|
|
50
|
Chen L, Tuo B, Dong H. Regulation of Intestinal Glucose Absorption by Ion Channels and Transporters. Nutrients 2016; 8:nu8010043. [PMID: 26784222 PMCID: PMC4728656 DOI: 10.3390/nu8010043] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 12/18/2015] [Accepted: 01/06/2016] [Indexed: 12/14/2022] Open
Abstract
The absorption of glucose is electrogenic in the small intestinal epithelium. The major route for the transport of dietary glucose from intestinal lumen into enterocytes is the Na+/glucose cotransporter (SGLT1), although glucose transporter type 2 (GLUT2) may also play a role. The membrane potential of small intestinal epithelial cells (IEC) is important to regulate the activity of SGLT1. The maintenance of membrane potential mainly depends on the activities of cation channels and transporters. While the importance of SGLT1 in glucose absorption has been systemically studied in detail, little is currently known about the regulation of SGLT1 activity by cation channels and transporters. A growing line of evidence suggests that cytosolic calcium ([Ca2+]cyt) can regulate the absorption of glucose by adjusting GLUT2 and SGLT1. Moreover, the absorption of glucose and homeostasis of Ca2+ in IEC are regulated by cation channels and transporters, such as Ca2+ channels, K+ channels, Na+/Ca2+ exchangers, and Na+/H+ exchangers. In this review, we consider the involvement of these cation channels and transporters in the regulation of glucose uptake in the small intestine. Modulation of them may be a potential strategy for the management of obesity and diabetes.
Collapse
Affiliation(s)
- Lihong Chen
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, and Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, and Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
| | - Hui Dong
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical College, and Digestive Disease Institute of Guizhou Province, Zunyi 563003, China.
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.
| |
Collapse
|