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Thakur S, Rawat P, Dehury B, Mondal P. TRIM32 regulates insulin sensitivity by controlling insulin receptor degradation in the liver. EMBO Rep 2025; 26:791-809. [PMID: 39747658 PMCID: PMC11811033 DOI: 10.1038/s44319-024-00348-7] [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: 01/17/2024] [Revised: 10/20/2024] [Accepted: 11/13/2024] [Indexed: 01/04/2025] Open
Abstract
Impaired insulin receptor signaling is strongly linked to obesity-related metabolic conditions like non-alcoholic fatty liver disease (NAFLD) and Type 2 diabetes (T2DM). However, the exact mechanisms behind impaired insulin receptor (INSR) signaling in obesity induced by a high-fat diet remain elusive. In this study, we identify an E3 ubiquitin ligase, tripartite motif-containing protein 32 (TRIM32), as a key regulator of hepatic insulin signaling that targets the insulin receptor (INSR) for ubiquitination and proteasomal degradation in high-fat diet (HFD) mice. HFD induces the nuclear translocation of SREBP-1c (Sterol Regulatory Element-Binding Protein 1c), resulting in increased expression of TRIM32 in hepatocytes. TRIM32 ubiquitylates INSR and facilitates its proteasomal degradation, leading to severe insulin resistance and fat accumulation within the liver of high-fat diet induced obese (DIO) mice. Conversely, liver-specific knockdown of TRIM32 enhances INSR expression and hepatic insulin sensitivity. Reduced AMPK signaling and phosphorylation of SREBP-1c at S372 in high-fat DIO mice promotes the nuclear translocation of SREBP-1c, leading to increased TRIM32 expression. In conclusion, our results demonstrate that TRIM32 promotes diet-induced hepatic insulin resistance by targeting the INSR to degradation.
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Affiliation(s)
- Shilpa Thakur
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, 175005, H.P., India
| | - Priya Rawat
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, 175005, H.P., India
| | - Budheswar Dehury
- Department of Bioinformatics, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, 576104, India
| | - Prosenjit Mondal
- School of Biosciences and Bioengineering, Indian Institute of Technology Mandi, Mandi, 175005, H.P., India.
- Department of Biological Sciences, Indian Institute of Science Education and Research Berhampur (IISER Berhampur), Berhampur, Odisha, 760010, India.
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2
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Takahashi A, Furuta H, Nishi H, Kamei H, Takahashi SI, Hakuno F. Insulin Receptor Substrate-2 Regulates the Secretion of Growth Factors in Response to Amino Acid Deprivation. Int J Mol Sci 2025; 26:841. [PMID: 39859555 PMCID: PMC11766276 DOI: 10.3390/ijms26020841] [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: 12/27/2024] [Revised: 01/16/2025] [Accepted: 01/18/2025] [Indexed: 01/27/2025] Open
Abstract
Insulin receptor substrates (IRSs) are well-known mediators of the insulin and insulin-like growth factor (IGF)-I signaling pathways. We previously reported that the protein levels of IRS-2, a molecular species of IRS, were upregulated in the livers of rats fed a protein-restricted diet. This study aimed to elucidate the physiological role of IRS-2, whose level increases in response to protein restriction in cultured hepatocyte models. Hepatocyte-derived cell lines subjected to amino acid deprivation showed increased IRS2 mRNA and IRS-2 protein levels due to increased IRS2 transcription and translation, respectively. Amino acid deprivation markedly increased vascular endothelial growth factor-D (VEGF-D) secretion. Remarkably, the amino acid deprivation-induced VEGF-D secretion was suppressed by IRS-2 knockdown and enhanced by IRS-2 overexpression. These results suggest that IRS-2 is an intercellular signaling molecule that extracellularly transmits information on amino acid deprivation stress by regulating the secretion of growth factors such as VEGF-D. Moreover, this function of IRS-2 is distinct from its currently accepted function as a mediator of the insulin/IGF-I signaling pathways. This study demonstrates that IRS-2 can modulate protein secretion in an insulin-independent manner and greatly expands our understanding of the role of IRS-2, which is upregulated in response to amino acid deprivation.
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Affiliation(s)
- Ayaka Takahashi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Haruka Furuta
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Hiroki Nishi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Saitama 338-8570, Japan
| | - Hiroyasu Kamei
- Faculty of Biological Science and Technology, Institute of Science and Engineering, Kanazawa University, Kanazawa 920-1192, Japan;
| | - Shin-Ichiro Takahashi
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
| | - Fumihiko Hakuno
- Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; (A.T.); (H.F.); (H.N.); (S.-I.T.)
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Toyoshima Y, Nakamura K, Taguchi Y, Tokita R, Takeuchi S, Osawa H, Teramoto N, Sugihara H, Yoshizawa F, Yamanouchi K, Minami S. Deletion of IRS-1 leads to growth failure and insulin resistance with downregulation of liver and muscle insulin signaling in rats. Sci Rep 2025; 15:649. [PMID: 39779784 PMCID: PMC11711447 DOI: 10.1038/s41598-024-84234-1] [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: 01/29/2024] [Accepted: 12/20/2024] [Indexed: 01/11/2025] Open
Abstract
Insulin receptor substrate (IRS)-1 and IRS-2 are major molecules that transduce signals from insulin and insulin-like growth factor-I receptors. The physiological functions of these proteins have been intensively investigated in mice, while little is known in other animals. Our previous study showed that the disruption of IRS-2 impairs body growth but not glucose tolerance or insulin sensitivity in rats, which led us to hypothesize that IRS-1 plays more pivotal roles in insulin functions than IRS-2. Here, we created IRS-1 knockout (KO) rats to elucidate the physiological roles of IRS-1 in rats. The body weight of IRS-1 KO rats at birth was lower than that of wild-type (WT) littermates, and postnatal growth of IRS-1 KO rats was severely impaired. Compared with WT rats, IRS-1 KO rats displayed insulin resistance but maintained euglycemia because of compensatory hyperinsulinemia. In addition, despite the increased activity of insulin-stimulated IRS-2-associated phosphatidylinositol-3 kinase (PI3K), insulin-induced phosphorylation of the kinases downstream of PI3K was suppressed in the liver and skeletal muscle of IRS-1 KO rats. Taken together, these results indicate that in rats, IRS-1 is essential for normal growth and the glucose-lowering effects of insulin. IRS-1 appears to be more important than IRS-2 for insulin functions in rats.
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Affiliation(s)
- Yuka Toyoshima
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan.
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan.
| | - Katsuyuki Nakamura
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Department of Chemistry and Biomolecular Science, Biomolecular Science Course, Faculty of Engineering, Gifu University, Gifu, Japan
| | - Yusuke Taguchi
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
| | - Reiko Tokita
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
| | - Shiho Takeuchi
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hayato Osawa
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan
| | - Naomi Teramoto
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Hidetoshi Sugihara
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Fumiaki Yoshizawa
- Department of Agrobiology and Bioresources, School of Agriculture, Utsunomiya University, 350 Mine-machi, Utsunomiya, 321-8505, Tochigi, Japan
| | - Keitaro Yamanouchi
- Laboratory of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Shiro Minami
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kawasaki, Kanagawa, Japan
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Kumar R, Gullapalli RR. Evaluating combined effects of chronic, low-dose exposures of cadmium (CLEC) and hyperglycemia on insulin signaling dysfunction in a hepatocellular model. Toxicology 2024; 508:153929. [PMID: 39191366 PMCID: PMC11573001 DOI: 10.1016/j.tox.2024.153929] [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: 06/06/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 08/29/2024]
Abstract
The pathophysiological effects of chronic heavy metal exposures on human health remains uncertain. In this study, we developed a novel chronic, low-dose exposure of Cadmium (CLEC) model using the hepatocellular cell lines, HepG2 and HUH7. We modulated cell culture conditions to mimic human normoglycemic (5.6 mM) and hyperglycemic (15 mM) states with concomitant cadmium (Cd) exposures for 24 weeks. CLEC cells undergo non-trivial alterations in glucose signaling and metabolic characteristics within our model. We observe elevated baseline reactive oxygen species (ROS) production and decreased 2-NBDG uptake indicative of glucose metabolic dysfunction. Additionally, induction of metallothionein (MT) expression, increased activation of Akt signaling (via phosphorylation) and reduced IRS-2 protein expression are observed in CLEC cells. Cell line specific changes are observed with HepG2 showing a much higher MT gene induction compared to HUH7 cell line which impacts glucose metabolic dysfunction. Hyperglycemic culture conditions (representing type II diabetes) significantly modulate CLEC effects on cells. In conclusion, pathophysiologically relevant models of chronic heavy metal exposures are urgently needed to gain an in-depth, mechanistic understanding of the long-term impacts of toxic metals (e.g., Cd) on human metabolic health.
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Affiliation(s)
- Rahul Kumar
- Department of Pathology, United States; Department of Chemical and Biological Engineering, Room 333A, MSC08-4640, University of New Mexico, Albuquerque, NM 87131, United States; Center for Metals in Biology and Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States
| | - Rama R Gullapalli
- Department of Pathology, United States; Department of Chemical and Biological Engineering, Room 333A, MSC08-4640, University of New Mexico, Albuquerque, NM 87131, United States; Center for Metals in Biology and Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, United States.
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Bergman M, Goshtchevsky U, Atlan T, Astre G, Halabi R, El H, Moses E, Lemus AJJ, Benayoun BA, Tzfati Y, Ben-Ami I, Harel I. The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.16.618655. [PMID: 39464159 PMCID: PMC11508313 DOI: 10.1101/2024.10.16.618655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes. While recent evidence suggests that inflammation, alongside mutation accumulation and cell death, may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here, by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish ( N. furzeri ), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly, mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also display reversal of telomere abnormalities and suppression of transposable elements, underscoring cGAS's non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic instability syndromes.
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Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab 2024; 36:947-968. [PMID: 38718757 DOI: 10.1016/j.cmet.2024.04.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/22/2024] [Accepted: 04/09/2024] [Indexed: 06/26/2024]
Abstract
Insulin resistance (IR) is a major pathogenic factor in the progression of MASLD. In the liver, insulin suppresses gluconeogenesis and enhances de novo lipogenesis (DNL). During IR, there is a defect in insulin-mediated suppression of gluconeogenesis, but an unrestrained increase in hepatic lipogenesis persists. The mechanism of increased hepatic steatosis in IR is unclear and remains controversial. The key discrepancy is whether insulin retains its ability to directly regulate hepatic lipogenesis. Blocking insulin/IRS/AKT signaling reduces liver lipid deposition in IR, suggesting insulin can still regulate lipid metabolism; hepatic glucose metabolism that bypasses insulin's action may contribute to lipogenesis; and due to peripheral IR, other tissues are likely to impact liver lipid deposition. We here review the current understanding of insulin's action in governing different aspects of hepatic lipid metabolism under normal and IR states, with the purpose of highlighting the essential issues that remain unsettled.
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Affiliation(s)
- Tao Bo
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Zhenyu Yao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Shanshan Shao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China
| | - Xuemin Wang
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia
| | - Christopher G Proud
- Lifelong Health, South Australian Health & Medical Research Institute, North Terrace, Adelaide, SA, Australia.
| | - Jiajun Zhao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, China.
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Tan Y, Zhou C, Miao L, Zhang X, Khan H, Xu B, Cheang WS. 3,4',5-Trimethoxy- trans-stilbene ameliorates hepatic insulin resistance and oxidative stress in diabetic obese mice through insulin and Nrf2 signaling pathways. Food Funct 2024; 15:2996-3007. [PMID: 38411214 DOI: 10.1039/d3fo04158a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
Resveratrol has profound benefits against diabetes. However, whether its methylated derivative 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) also plays a protective role in glucose metabolism is not characterized. We aimed to study the anti-diabetic effects of 3,4',5-TMS in vitro and in vivo. Insulin-resistant HepG2 cells (IR-HepG2) were induced by high glucose plus dexamethasone whilst six-week-old male C57BL/6J mice received a 60 kcal% fat diet for 14 weeks to establish an obese diabetic model. 3,4',5-TMS did not reduce the cell viability of IR-HepG2 cells at concentrations of 0.5 and 1 μM, which enhanced the capability of glycogen synthesis and glucose consumption in IR-HepG2 cells. Four-week oral administration of 3,4',5-TMS at 10 mg kg-1 day-1 ameliorated insulin sensitivity and glucose tolerance of diet-induced obese (DIO) mice. 3,4',5-TMS activated the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway by inhibiting phosphorylation of insulin receptor substrate (IRS)-1 at Ser307 and increasing the protein levels of IRS-1 and IRS-2 to restore the insulin signaling pathway in diabetes. 3,4',5-TMS also upregulated the phosphorylation of glycogen synthase kinase 3 beta (GSK3β) at Ser9. 3,4',5-TMS suppressed oxidative stress by increasing the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H : quinone oxidoreductase 1 (NQO1) and antioxidant enzyme activity. In summary, 3,4',5-TMS alleviated hepatic insulin resistance in vitro and in vivo, by the activation of the insulin signaling pathway, accomplished by the suppression of oxidative stress.
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Affiliation(s)
- Yi Tan
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
| | - Chunxiu Zhou
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
| | - Lingchao Miao
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
| | - Xutao Zhang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan 23200, Pakistan
| | - Baojun Xu
- Food Science and Technology Program, BNU-HKBU United International College, Zhuhai, Guangdong, China.
| | - Wai San Cheang
- Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau SAR, China.
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Sakr HF, Sirasanagandla SR, Das S, Bima AI, Elsamanoudy AZ. Insulin Resistance and Hypertension: Mechanisms Involved and Modifying Factors for Effective Glucose Control. Biomedicines 2023; 11:2271. [PMID: 37626767 PMCID: PMC10452601 DOI: 10.3390/biomedicines11082271] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 07/18/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Factors such as aging, an unhealthy lifestyle with decreased physical activity, snacking, a standard Western diet, and smoking contribute to raising blood pressure to a dangerous level, increasing the risk of coronary artery disease and heart failure. Atherosclerosis, or aging of the blood vessels, is a physiological process that has accelerated in the last decades by the overconsumption of carbohydrates as the primary sources of caloric intake, resulting in increased triglycerides and VLDL-cholesterol and insulin spikes. Classically, medications ranging from beta blockers to angiotensin II blockers and even calcium channel blockers were used alone or in combination with lifestyle modifications as management tools in modern medicine to control arterial blood pressure. However, it is not easy to control blood pressure or the associated complications. A low-carbohydrate, high-fat (LCHF) diet can reduce glucose and insulin spikes, improve insulin sensitivity, and lessen atherosclerosis risk factors. We reviewed articles describing the etiology of insulin resistance (IR) and its impact on arterial blood pressure from databases including PubMed, PubMed Central, and Google Scholar. We discuss how the LCHF diet is beneficial to maintaining arterial blood pressure at normal levels, slowing down the progression of atherosclerosis, and reducing the use of antihypertensive medications. The mechanisms involved in IR associated with hypertension are also highlighted.
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Affiliation(s)
- Hussein F. Sakr
- Department of Physiology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman
| | - Srinivasa Rao Sirasanagandla
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; (S.R.S.); (S.D.)
| | - Srijit Das
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Oman; (S.R.S.); (S.D.)
| | - Abdulhadi I. Bima
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21465, Saudi Arabia; (A.I.B.); (A.Z.E.)
| | - Ayman Z. Elsamanoudy
- Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21465, Saudi Arabia; (A.I.B.); (A.Z.E.)
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Jiang Y, Zhuang Z, Jia W, Wen Z, Xie M, Bai H, Bi Y, Wang Z, Chang G, Hou S, Chen G. Proteomic and phosphoproteomic analysis reveal threonine deficiency increases hepatic lipid deposition in Pekin ducks via reducing STAT phosphorylation. ANIMAL NUTRITION 2023; 13:249-260. [PMID: 37168449 PMCID: PMC10164787 DOI: 10.1016/j.aninu.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 01/16/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023]
Abstract
Dietary threonine (Thr) deficiency enhances triglyceride (TG) deposition in the liver of Pekin ducks, which injures hepatic function and impairs growth performance. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the effects of dietary Thr deficiency on the expressions of proteins and phosphoproteins in liver of Pekin ducks, to identify the underlying molecular changes. A total of 300 one-day-old ducklings were divided into 3 groups with 10 replicates of 10 birds. All ducks were fed corn-wheat-peanut meal diets containing 0.46%, 0.71%, and 0.96% Thr, respectively, from 1 to 21 days of age. Growth performance, serum parameters, hepatic TG content, and expression of genes involved in lipid metabolism of Pekin ducks were determined. A Thr deficiency group (Thr-D, 0.46% Thr) and a Thr sufficiency group (Thr-S, 0.71% Thr) were selected for subsequent proteomic and phosphoproteomic analysis. The results showed that Thr-D reduced the growth performance (P < 0.001), and increased the plasma concentrations of cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and hepatic TG (P < 0.05). Thr-D increased gene expression related to fatty acid and TG synthesis (P < 0.05). A total of 176 proteins and 259 phosphosites (containing 198 phosphoproteins) were observed to be differentially expressed as a result of Thr-D. The upregulated proteins were enriched in the pathway related to amino acid metabolism, peroxisome. The downregulated proteins were enriched in linolenic and arachidonic acid metabolism, and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. The upregulated phosphoproteins were enriched in the pathways related to fatty acid biosynthesis, fructose and mannose metabolism, and glycolysis/gluconeogenesis. Thr-D reduced the phosphorylation of STAT1 at S729 and STAT3 at S728, and expression of STAT5B. In contrast, Thr-D increased non-receptor tyrosine-protein kinase (TYK2) expression and STAT1 phosphorylation at S649. Taken together, dietary Thr-D increased hepatic TG accumulation by upregulating the expression of genes and proteins, and phosphoproteins related to fatty acid and triglyceride synthesis. Furthermore, these processes might be regulated by the JAK-STAT signaling pathway, especially the phosphorylation of STAT1 and STAT3.
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Goode RA, Hum JM, Kalwat MA. Therapeutic Strategies Targeting Pancreatic Islet β-Cell Proliferation, Regeneration, and Replacement. Endocrinology 2022; 164:6836713. [PMID: 36412119 PMCID: PMC9923807 DOI: 10.1210/endocr/bqac193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/16/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022]
Abstract
Diabetes results from insufficient insulin production by pancreatic islet β-cells or a loss of β-cells themselves. Restoration of regulated insulin production is a predominant goal of translational diabetes research. Here, we provide a brief overview of recent advances in the fields of β-cell proliferation, regeneration, and replacement. The discovery of therapeutic targets and associated small molecules has been enabled by improved understanding of β-cell development and cell cycle regulation, as well as advanced high-throughput screening methodologies. Important findings in β-cell transdifferentiation, neogenesis, and stem cell differentiation have nucleated multiple promising therapeutic strategies. In particular, clinical trials are underway using in vitro-generated β-like cells from human pluripotent stem cells. Significant challenges remain for each of these strategies, but continued support for efforts in these research areas will be critical for the generation of distinct diabetes therapies.
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Affiliation(s)
- Roy A Goode
- Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA
| | - Julia M Hum
- Division of Biomedical Sciences, College of Osteopathic Medicine, Marian University, Indianapolis, IN, USA
| | - Michael A Kalwat
- Correspondence: Michael A. Kalwat, PhD, Lilly Diabetes Center of Excellence, Indiana Biosciences Research Institute, 1210 Waterway Blvd, Suite 2000, Indianapolis, IN 46202, USA. or
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Hypoglycemic Effect of Exopolysaccharide from Lactiplantibacillus plantarum JLAU103 on Streptozotocin and High-Fat Diet-Induced Type 2 Diabetic Mice. Foods 2022; 11:foods11223571. [PMID: 36429163 PMCID: PMC9689433 DOI: 10.3390/foods11223571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/07/2022] [Accepted: 11/08/2022] [Indexed: 11/11/2022] Open
Abstract
Two doses (300 mg/kg bw and 600 mg/kg bw) of the Lactiplantibacillus plantarum JLAU103 exopolysaccharide (EPS103) were orally administered to a type 2 diabetic (T2DM) mouse model induced by streptozotocin and a high-fat diet. The hypoglycemic, hypolipidemic and neuroprotective effects of EPS103 on T2DM mice were evaluated. The results indicated that administration of EPS103 could alleviate insulin resistance, reduce the levels of fasting blood glucose, glycosylated hemoglobin A1c, leptin and fasting serum insulin, improve glucose tolerance, protect pancreas and liver, and modulate blood lipid disorders. EPS103 promoted hepatic glycogen synthesis by upregulating the phosphorylation of GSK3β. Meanwhile, it upregulated the phosphorylation of IRS-1, PI3K and Akt, as well as the expression of IRS-2 and GLUT4, and downregulated the expression of PEPCK, G6Pase and PGC-1α, indicating that EPS103 promotes the uptake and transport of glucose and inhibits gluconeogenesis, which might be related to the activation of the IRS-1/PI3K/Akt pathway. Additionally, EPS103 can protect against brain nerve damage through improving oxidative stress injury, restoring the expression of IRS-2, alleviating neuronal apoptosis and inhibiting inflammation in the hippocampus of T2DM mice. Taken together, our results demonstrated that EPS103 may be a potential therapeutic agent for the treatment of T2DM.
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Ramasubbu K, Devi Rajeswari V. Impairment of insulin signaling pathway PI3K/Akt/mTOR and insulin resistance induced AGEs on diabetes mellitus and neurodegenerative diseases: a perspective review. Mol Cell Biochem 2022; 478:1307-1324. [PMID: 36308670 DOI: 10.1007/s11010-022-04587-x] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 10/12/2022] [Indexed: 12/01/2022]
Abstract
Insulin resistance is common in type 2 diabetes mellitus (T2DM), neurodegenerative diseases, cardiovascular diseases, kidney diseases, and polycystic ovary syndrome. Impairment in insulin signaling pathways, such as the PI3K/Akt/mTOR pathway, would lead to insulin resistance. It might induce the synthesis and deposition of advanced glycation end products (AGEs), reactive oxygen species, and reactive nitrogen species, resulting in stress, protein misfolding, protein accumulation, mitochondrial dysfunction, reticulum function, and metabolic syndrome dysregulation, inflammation, and apoptosis. It plays a huge role in various neurodegenerative diseases like Parkinson's disease, Alzheimer's disease, Huntington's disease, and Amyloid lateral sclerosis. In this review, we intend to focus on the possible effect of insulin resistance in the progression of neurodegeneration via the impaired P13K/Akt/mTOR signaling pathway, AGEs, and receptors for AGEs.
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Affiliation(s)
- Kanagavalli Ramasubbu
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India
| | - V Devi Rajeswari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632014, India.
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13
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Wang Y, Song X, Wang Y, Wang N. Specific interaction of insulin receptor and GLP-1 receptor mediates crosstalk between their signaling. Biochem Biophys Res Commun 2022; 636:31-39. [DOI: 10.1016/j.bbrc.2022.10.094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/02/2022]
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14
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Seesen M, Pratchayasakul W, Pintana H, Chattipakorn N, Chattipakorn SC. Exposure to organophosphates in association with the development of insulin resistance: Evidence from in vitro, in vivo, and clinical studies. Food Chem Toxicol 2022; 168:113389. [PMID: 36031162 DOI: 10.1016/j.fct.2022.113389] [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: 04/26/2022] [Revised: 07/21/2022] [Accepted: 08/19/2022] [Indexed: 10/15/2022]
Abstract
Insulin resistance is an underlying condition prior to the development of several diseases, including type 2 diabetes, cardiovascular diseases, cognitive impairment, and cerebrovascular complications. Organophosphates (OPs) are one of several factors thought to induce insulin resistance. Previous studies showed that the exposure to OPs pesticides induced insulin resistance through the impairment of hepatic glucose metabolism, pancreatic damage, and disruption of insulin signaling of both adipose tissues and skeletal muscles. Several studies reported possible mechanisms associated with OPs-induced insulin resistance in different models in in vivo studies including those in adult animals, obese animals, and offspring models, as well as in clinical studies. In addition, pharmacological interventions in OPs-induced insulin resistance have been previously investigated. This review aims to summarize and discuss all the evidence concerning OPs-induced insulin resistance in different models including in vitro, in vivo and clinical studies. The interventions of OPs-induced insulin resistance are also discussed. Any contradictory findings also considered. The information from this review will provide insight for possible therapeutic approaches to OPs-induced insulin resistance in the future.
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Affiliation(s)
- Mathuramat Seesen
- Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Wasana Pratchayasakul
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Hiranya Pintana
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
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15
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De Meyts P. [The insulin receptor discovery is 50 years old - A review of achieved progress]. Biol Aujourdhui 2022; 216:7-28. [PMID: 35876517 DOI: 10.1051/jbio/2022007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Indexed: 06/15/2023]
Abstract
The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.
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Affiliation(s)
- Pierre De Meyts
- de Duve Institute, Department of Cell Signalling, Avenue Hippocrate 74, B-1200 Bruxelles, Belgique - Novo Nordisk A/S, Department of Stem Cell Research, Novo Nordisk Park 1, DK-2760 Maaloev, Danemark
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16
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Speelman T, Dale L, Louw A, Verhoog NJD. The Association of Acute Phase Proteins in Stress and Inflammation-Induced T2D. Cells 2022; 11:2163. [PMID: 35883605 PMCID: PMC9321356 DOI: 10.3390/cells11142163] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/02/2022] [Accepted: 07/04/2022] [Indexed: 02/06/2023] Open
Abstract
Acute phase proteins (APPs), such as plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), and C-reactive protein (CRP), are elevated in type-2 diabetes (T2D) and are routinely used as biomarkers for this disease. These APPs are regulated by the peripheral mediators of stress (i.e., endogenous glucocorticoids (GCs)) and inflammation (i.e., pro-inflammatory cytokines), with both implicated in the development of insulin resistance, the main risk factor for the development of T2D. In this review we propose that APPs, PAI-1, SAA, and CRP, could be the causative rather than only a correlative link between the physiological elements of risk (stress and inflammation) and the development of insulin resistance.
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Affiliation(s)
| | | | | | - Nicolette J. D. Verhoog
- Biochemistry Department, Stellenbosch University, Van der Byl Street, Stellenbosch 7200, South Africa; (T.S.); (L.D.); (A.L.)
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17
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Phase separation of insulin receptor substrate 1 drives the formation of insulin/IGF-1 signalosomes. Cell Discov 2022; 8:60. [PMID: 35764611 PMCID: PMC9240053 DOI: 10.1038/s41421-022-00426-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 05/27/2022] [Indexed: 11/25/2022] Open
Abstract
As a critical node for insulin/IGF signaling, insulin receptor substrate 1 (IRS-1) is essential for metabolic regulation. A long and unstructured C-terminal region of IRS-1 recruits downstream effectors for promoting insulin/IGF signals. However, the underlying molecular basis for this remains elusive. Here, we found that the C-terminus of IRS-1 undergoes liquid-liquid phase separation (LLPS). Both electrostatic and hydrophobic interactions were seen to drive IRS-1 LLPS. Self-association of IRS-1, which was mainly mediated by the 301–600 region, drives IRS-1 LLPS to form insulin/IGF-1 signalosomes. Moreover, tyrosine residues of YXXM motifs, which recruit downstream effectors, also contributed to IRS-1 self-association and LLPS. Impairment of IRS-1 LLPS attenuated its positive effects on insulin/IGF-1 signaling. The metabolic disease-associated G972R mutation impaired the self-association and LLPS of IRS-1. Our findings delineate a mechanism in which LLPS of IRS-1-mediated signalosomes serves as an organizing center for insulin/IGF-1 signaling and implicate the role of aberrant IRS-1 LLPS in metabolic diseases.
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18
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Liu X, Liang Z, Duan H, Yu J, Qin Z, Li J, Zhu L, Wu Q, Xiao W, Shen C, Wan C, Wu K, Ye H, Zhang B, Zhao W. Dengue virus is involved in insulin resistance via the downregulation of IRS-1 by inducing TNF-α secretion. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166472. [PMID: 35752384 DOI: 10.1016/j.bbadis.2022.166472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/29/2022]
Abstract
During the epidemic, the individuals with underlying diseases usually have a higher rate of mortality. Diabetes is highly prevalent worldwide, making it a frequent comorbidity in dengue fever patients. Therefore, understanding the relationship between dengue virus (DENV) infection and diabetes is important. We first demonstrated that DENV-3 infection down-regulated the expression of IRS-1. In vitro, treatment of HepG2 cells with TNF-α inhibitors and siRNA proved that after DENV-3 infection in HepG2 cells, cellular TNF-α secretion was increased, which negatively regulated IRS-1, thereby leading to an insulin-resistant state. In vivo, DENV-3 induced insulin resistance (IR) in hepatocytes by promoting the secretion of TNF-α and inhibiting the expression of IRS-1 was proved. In vivo approaches also showed that after DENV-3 infection, TNF-α levels in the serum of C57BL/6 mice with insulin resistance increased, and upon TNF-α antagonist III treatment, IRS-1 expression in the liver, reduced by infection, was upregulated. In addition, transcriptomic analysis revealed more negative regulatory events in the insulin receptor signaling pathway after DENV-3 infection. This is the first report of a link between DENV-3 infection and insulin resistance, and it lays a foundation for further research.
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Affiliation(s)
- Xuling Liu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zuxin Liang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Hongwei Duan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jianhai Yu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Zhiran Qin
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Jingshu Li
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Li Zhu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Qinghua Wu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Weiwei Xiao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chenguang Shen
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Chengsong Wan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Kefeng Wu
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China
| | - Hua Ye
- Guangdong Key Laboratory for Research and Development of Natural Drugs, The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang 524023, China.
| | - Bao Zhang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
| | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
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19
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Chen YZ, Gu J, Chuang WT, Du YF, Zhang L, Lu ML, Xu JY, Li HQ, Liu Y, Feng HT, Li YH, Qin LQ. Slowly Digestible Carbohydrate Diet Ameliorates Hyperglycemia and Hyperlipidemia in High-Fat Diet/Streptozocin-Induced Diabetic Mice. Front Nutr 2022; 9:854725. [PMID: 35495933 PMCID: PMC9051025 DOI: 10.3389/fnut.2022.854725] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
Objective Given that the prevalence rate of type 2 diabetes mellitus (T2DM) continues to increase, it is important to find an effective method to prevent or treat this disease. Previous studies have shown that dietary intervention with a slowly digestible carbohydrate (SDC) diet can improve T2DM with almost no side effects. However, the underlying mechanisms of SDC protect against T2DM remains to be elucidated. Methods The T2DM mice model was established with a high-fat diet and streptozocin injection. Then, SDC was administered for 6 weeks. Bodyweight, food intake, organ indices, fasting blood glucose (FBG), oral glucose tolerance test (OGTT), homeostasis model assessment for insulin resistance (HOMA-IR), and other biochemical parameters were measured. Histopathological and lipid accumulation analyses were performed, and the glucose metabolism-related gene expressions in the liver and skeletal muscle were determined. Lastly, colonic microbiota was also analyzed. Results SDC intervention alleviated the weight loss in the pancreas, lowered blood glucose and glycosylated hemoglobin levels, and improved glucose tolerance and HOMA-IR. SDC intervention improved serum lipid profile, adipocytokines levels, and lowered the lipid accumulation in the liver, subcutaneous adipose tissue, and epididymal visceral adipose tissue. In addition, SDC intervention increased the expression levels of IRS-2 and GLUT-2 in liver tissues and elevated GLUT-4 expression levels in skeletal muscle tissues. Notably, SDC intervention decreased the Bacteroidetes/Firmicutes ratio, increased Desulfovibrio and Lachnospiraceae genus levels, and inhibited the relative abundance of potentially pathogenic bacteria. Conclusions SDC intervention can improve hyperglycemia and hyperlipidemia status in diabetic mice, suggesting that this intervention might be beneficial for T2DM.
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Affiliation(s)
- Yu-Zhong Chen
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Jia Gu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Wei-Ting Chuang
- Inner Mongolia Dairy Technology Research Institute Co., Ltd., Hohhot, China
| | - Ya-Fang Du
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Lin Zhang
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Meng-Lan Lu
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou, China
| | - Hao-Qiu Li
- Inner Mongolia Dairy Technology Research Institute Co., Ltd., Hohhot, China
| | - Yan Liu
- Inner Mongolia Dairy Technology Research Institute Co., Ltd., Hohhot, China
| | - Hao-Tian Feng
- Inner Mongolia Dairy Technology Research Institute Co., Ltd., Hohhot, China
- *Correspondence: Hao-Tian Feng
| | - Yun-Hong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
- Yun-Hong Li
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China
- Li-Qiang Qin
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20
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Skovsø S, Panzhinskiy E, Kolic J, Cen HH, Dionne DA, Dai XQ, Sharma RB, Elghazi L, Ellis CE, Faulkner K, Marcil SAM, Overby P, Noursadeghi N, Hutchinson D, Hu X, Li H, Modi H, Wildi JS, Botezelli JD, Noh HL, Suk S, Gablaski B, Bautista A, Kim R, Cras-Méneur C, Flibotte S, Sinha S, Luciani DS, Nislow C, Rideout EJ, Cytrynbaum EN, Kim JK, Bernal-Mizrachi E, Alonso LC, MacDonald PE, Johnson JD. Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat Commun 2022; 13:735. [PMID: 35136059 PMCID: PMC8826929 DOI: 10.1038/s41467-022-28039-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 01/05/2022] [Indexed: 01/23/2023] Open
Abstract
Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.
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Affiliation(s)
- Søs Skovsø
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Evgeniy Panzhinskiy
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jelena Kolic
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Haoning Howard Cen
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Derek A Dionne
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Xiao-Qing Dai
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Rohit B Sharma
- Division of Endocrinology, Diabetes and Metabolism and the Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
| | - Lynda Elghazi
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, Ann Arbor, MI, USA
| | - Cara E Ellis
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Katharine Faulkner
- Department of Mathematics, University of British Columbia, Vancouver, BC, Canada
| | - Stephanie A M Marcil
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Peter Overby
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Nilou Noursadeghi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Daria Hutchinson
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Xiaoke Hu
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Hong Li
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Honey Modi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Jennifer S Wildi
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - J Diego Botezelli
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Hye Lim Noh
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
- Charles River Laboratories, Shrewsbury, MA, USA
| | - Sujin Suk
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
| | - Brian Gablaski
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
- Charles River Laboratories, Shrewsbury, MA, USA
| | - Austin Bautista
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Ryekjang Kim
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - Corentin Cras-Méneur
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Stephane Flibotte
- UBC Life Sciences Institute Bioinformatics Facility, University of British Columbia, Vancouver, BC, Canada
| | - Sunita Sinha
- UBC Sequencing and Bioinformatics Consortium, Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Dan S Luciani
- BC Children's Hospital Research Institute, Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Corey Nislow
- UBC Sequencing and Bioinformatics Consortium, Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Elizabeth J Rideout
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Eric N Cytrynbaum
- Department of Mathematics, University of British Columbia, Vancouver, BC, Canada
| | - Jason K Kim
- Program in Molecular Medicine University of Massachusetts Medical School, Worcester, MA, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Ernesto Bernal-Mizrachi
- Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine and Miami VA Health Care System, Miami, FL, USA
| | - Laura C Alonso
- Division of Endocrinology, Diabetes and Metabolism and the Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA
| | - Patrick E MacDonald
- Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada
| | - James D Johnson
- Diabetes Research Group, Life Sciences Institute, and Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
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21
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Long W, Zhou T, Xuan X, Cao Q, Luo Z, Qin Y, Ning Q, Luo X, Xie X. IUGR with catch-up growth programs impaired insulin sensitivity through LRP6/IRS-1 in male rats. Endocr Connect 2022; 11:EC-21-0203.R1. [PMID: 34825892 PMCID: PMC8789020 DOI: 10.1530/ec-21-0203] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/26/2021] [Indexed: 11/11/2022]
Abstract
Intrauterine growth restriction combined with postnatal accelerated growth (CG-IUGR) could lead to long-term detrimental metabolic outcomes characterized by insulin resistance. As an indispensable co-receptor of Wnt signaling, LRP6 plays a critical role in the susceptibility of metabolic disorders. However, whether LRP6 is involved in the metabolic programing is still unknown. We hypothesized that CG-IUGR programed impaired insulin sensitivity through the impaired LRP6-mediated Wnt signaling in skeletal muscle. A CG-IUGR rat model was employed. The transcriptional and translational alterations of the components of the Wnt and the insulin signaling in the skeletal muscle of the male CG-IUGR rats were determined. The role of LRP6 on the insulin signaling was evaluated by shRNA knockdown or Wnt3a stimulation of LRP6. Compared with controls, the male CG-IUGR rats showed an insulin-resistant phenotype, with impaired insulin signaling and decreased expression of LRP6/β-catenin in skeletal muscle. LRP6 knockdown led to reduced expression of the IR-β/IRS-1 in C2C12 cell line, while Wnt3a-mediated LRP6 expression increased the expression of IRS-1 and IGF-1R but not IR-β in the primary muscle cells of male CG-IUGR rats. The impaired LRP6/β-catenin/IGF-1R/IRS-1 signaling is probably one of the critical mechanisms underlying the programed impaired insulin sensitivity in male CG-IUGR.
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Affiliation(s)
- Wenjun Long
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Tuo Zhou
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiuping Xuan
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qiuli Cao
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zuojie Luo
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Yingfen Qin
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qin Ning
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoping Luo
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xuemei Xie
- Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Correspondence should be addressed to X Xie:
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22
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Ertuglu LA, Elijovich F, Laffer CL, Kirabo A. Salt-Sensitivity of Blood Pressure and Insulin Resistance. Front Physiol 2021; 12:793924. [PMID: 34966295 PMCID: PMC8711096 DOI: 10.3389/fphys.2021.793924] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 11/18/2021] [Indexed: 12/20/2022] Open
Abstract
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.
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Affiliation(s)
- Lale A Ertuglu
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Fernando Elijovich
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cheryl L Laffer
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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23
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Ghiasi SM, Rutter GA. Consequences for Pancreatic β-Cell Identity and Function of Unregulated Transcript Processing. Front Endocrinol (Lausanne) 2021; 12:625235. [PMID: 33763030 PMCID: PMC7984428 DOI: 10.3389/fendo.2021.625235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/26/2021] [Indexed: 12/25/2022] Open
Abstract
Mounting evidence suggests a role for alternative splicing (AS) of transcripts in the normal physiology and pathophysiology of the pancreatic β-cell. In the apparent absence of RNA repair systems, RNA decay pathways are likely to play an important role in controlling the stability, distribution and diversity of transcript isoforms in these cells. Around 35% of alternatively spliced transcripts in human cells contain premature termination codons (PTCs) and are targeted for degradation via nonsense-mediated decay (NMD), a vital quality control process. Inflammatory cytokines, whose levels are increased in both type 1 (T1D) and type 2 (T2D) diabetes, stimulate alternative splicing events and the expression of NMD components, and may or may not be associated with the activation of the NMD pathway. It is, however, now possible to infer that NMD plays a crucial role in regulating transcript processing in normal and stress conditions in pancreatic β-cells. In this review, we describe the possible role of Regulated Unproductive Splicing and Translation (RUST), a molecular mechanism embracing NMD activity in relationship to AS and translation of damaged transcript isoforms in these cells. This process substantially reduces the abundance of non-functional transcript isoforms, and its dysregulation may be involved in pancreatic β-cell failure in diabetes.
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Affiliation(s)
- Seyed M. Ghiasi
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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24
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Quantitative proteomics and phosphoproteomic analyses of mouse livers after tick-borne Babesia microti infection. Int J Parasitol 2020; 51:167-182. [PMID: 33242464 DOI: 10.1016/j.ijpara.2020.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 09/02/2020] [Accepted: 09/03/2020] [Indexed: 12/15/2022]
Abstract
Babesia microti is a tick-borne protozoan parasite that infects the red blood cells of mice, humans, and other mammals. The liver tissues of BALB/c mice infected with B. microti exhibit severe injury. To further investigate the molecular mechanisms underlying liver injury and liver self-repair after B. microti infection, data-independent acquisition (DIA) quantitative proteomics was used to analyse changes in the expression and phosphorylation of proteins in liver tissues of BALB/c mice during a B. microti infection period and a recovery period. The expression of FABP1 and ACBP, which are related to fatty acid transport in the liver, was downregulated after infection with B. microti, as was the expression of Acox1, Ehhadh and Acaa1a, which are crucial rate-limiting enzymes in the process of fatty acid β oxidation. The phosphorylation levels of AMP-activated protein kinase (AMPK) and Hormone-sensitive lipase (HSL) were also downregulated. In addition, the expression of PSMB9, CTSC, and other immune-related proteins was increased, reflecting an active immune regulation mechanism in the mice. The weights of mice infected with B. microti were significantly reduced, and the phosphorylation levels of IRS-1, c-Raf, mTOR, and other proteins related to growth and development were downregulated.
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25
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Cemeroglu AP, Sarialioglu F, Belen-Apak FB, Terzi YK. Persistent Hyperinsulinemic Hypoglycemia with Pancreatic Teratoma in Infancy: A Case Report. AMERICAN JOURNAL OF CASE REPORTS 2020; 21:e925273. [PMID: 32782239 PMCID: PMC7447291 DOI: 10.12659/ajcr.925273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Patient: Female, 6-month-old Final Diagnosis: Hyperinsulinemic hypoglycemia with abdominal teratoma Symptoms: Hypoglycemia Medication: — Clinical Procedure: Surgery removal Specialty: Endocrinology and Metabolic
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Affiliation(s)
- Ayse Pinar Cemeroglu
- Deparment of Pediatric Endocrinology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Faik Sarialioglu
- Deparment of Pediatric Hematology Oncology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Fatma Burcu Belen-Apak
- Deparment of Pediatric Hematology Oncology, Faculty of Medicine, Baskent University, Ankara, Turkey
| | - Yunus Kasim Terzi
- Deparment of Clinical Genetics, Faculty of Medicine, Baskent University, Ankara, Turkey
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26
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Toyoshima Y, Nakamura K, Tokita R, Teramoto N, Sugihara H, Kato H, Yamanouchi K, Minami S. Disruption of insulin receptor substrate-2 impairs growth but not insulin function in rats. J Biol Chem 2020; 295:11914-11927. [PMID: 32631952 DOI: 10.1074/jbc.ra120.013095] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 07/01/2020] [Indexed: 11/06/2022] Open
Abstract
Insulin receptor substrate (IRS)-2, along with IRS-1, is a key signaling molecule that mediates the action of insulin and insulin-like growth factor (IGF)-I. The activated insulin and IGF-I receptors phosphorylate IRSs on tyrosine residues, leading to the activation of downstream signaling pathways and the induction of various physiological functions of insulin and IGF-I. Studies using IRS-2 knockout (KO) mice showed that the deletion of IRS-2 causes type 2 diabetes due to peripheral insulin resistance and impaired β-cell function. However, little is known about the roles of IRS-2 in other animal models. Here, we created IRS-2 KO rats to elucidate the physiological functions of IRS-2 in rats. The body weights of IRS-2 KO rats at birth were lower compared with those of their WT littermates. The postnatal growth of both male and female IRS-2 KO rats was also suppressed. Compared with male WT rats, the glucose and insulin tolerance of male IRS-2 KO rats were slightly enhanced, whereas a similar difference was not observed between female WT and IRS-2 KO rats. Besides the modestly increased insulin sensitivity, male IRS-2 KO rats displayed the enhanced insulin-induced activation of the mTOR complex 1 pathway in the liver compared with WT rats. Taken together, these results indicate that in rats, IRS-2 plays important roles in the regulation of growth but is not essential for the glucose-lowering effects of insulin.
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Affiliation(s)
- Yuka Toyoshima
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
| | - Katsuyuki Nakamura
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Reiko Tokita
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
| | - Naomi Teramoto
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Hidetoshi Sugihara
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Hisanori Kato
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Keitaro Yamanouchi
- Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo, Japan
| | - Shiro Minami
- Department of Bioregulation, Institute for Advanced Medical Sciences, Nippon Medical School, Kosugi-machi, Nakahara-ku, Kawasaki, Japan
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27
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Polymorphism analysis of the Gly972Arg IRS-1 and Gly1057Asp IRS-2 genes in obese pregnant women. Reprod Biol 2020; 20:365-370. [PMID: 32540195 DOI: 10.1016/j.repbio.2020.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/27/2020] [Accepted: 05/08/2020] [Indexed: 11/21/2022]
Abstract
Genes encoding insulin receptor substrates IRS-1 and IRS-2 perform key functions in the insulin pathway. Numerous authors have suggested that single-nucleotide polymorphism (SNP) changes in the DNA sequence may be associated with the development of obesity, insulin resistance and type 2 diabetes. The Gly972Arg polymorphism of the IRS-1 gene and the Gly1057Asp polymorphism of the IRS-2 gene are believed to be associated with the occurrence of insulin resistance and obesity according to many sources. The aim of our study was to investigate the influence of these polymorphisms on the clinical parameters and to assess their correlations in obese Polish pregnant women. A total of 154 pregnant Caucasian women from the Wielkopolska region were analyzed: 78 diagnosed with overweight or obesity (study group) and 76 with normal body mass (controls). The analysis of the polymorphisms was performed using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. The IRS-2 Gly1057Asp polymorphism revealed no significant correlations with excessive weight gain during pregnancy. The analysis of the IRS-1 Gly972Arg polymorphism showed an association with obesity between the study and control groups (GG-80.77%, GR-17.95%, RR-1.28% vs GG-94.74%, GR-5.26%; p = 0.023). We also observed slightly increased BMI values and higher values of the waist and hip circumference before pregnancy in the case of the IRS-1 Gly972Arg polymorphism. The analysis of the clinical and anthropometric parameters demonstrated no significant relationships between the genotypes of the polymorphic variants of the IRS-1 and IRS-2 genes but suggested an association between the IRS-1 Gly972Arg polymorphism and the risk for obesity.
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28
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Tan HY, Tan SL, Teo SH, Roebuck MM, Frostick SP, Kamarul T. Development of a novel in vitro insulin resistance model in primary human tenocytes for diabetic tendinopathy research. PeerJ 2020; 8:e8740. [PMID: 32587790 PMCID: PMC7304430 DOI: 10.7717/peerj.8740] [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: 08/21/2019] [Accepted: 02/12/2020] [Indexed: 11/20/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy. Methods hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis. Results Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF–α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h. Conclusion At 0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy.
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Affiliation(s)
- Hui Yee Tan
- Tissue Engineering Group (TEG), National Orthopaedics Centre of Excellent Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Federal Territory, Malaysia
| | - Sik Loo Tan
- Tissue Engineering Group (TEG), National Orthopaedics Centre of Excellent Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Federal Territory, Malaysia
| | - Seow Hui Teo
- National Orthopaedic Centre of Excellence for Research and Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Federal Territory, Malaysia
| | - Margaret M Roebuck
- Musculoskeletal Science Research Group, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, Other, United Kingdom
| | - Simon P Frostick
- Musculoskeletal Science Research Group, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, Other, United Kingdom
| | - Tunku Kamarul
- Tissue Engineering Group (TEG), National Orthopaedics Centre of Excellent Research & Learning (NOCERAL), Department of Orthopaedic Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Federal Territory, Malaysia
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29
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Kanno A, Asahara SI, Furubayashi A, Masuda K, Yoshitomi R, Suzuki E, Takai T, Kimura-Koyanagi M, Matsuda T, Bartolome A, Hirota Y, Yokoi N, Inaba Y, Inoue H, Matsumoto M, Inoue K, Abe T, Wei FY, Tomizawa K, Ogawa W, Seino S, Kasuga M, Kido Y. GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels. JCI Insight 2020; 5:128820. [PMID: 32376799 DOI: 10.1172/jci.insight.128820] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 04/01/2020] [Indexed: 01/09/2023] Open
Abstract
EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass. Our data suggest that GCN2 senses amino acid deficiency in β cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent β cell failure during the consumption of a high-fat diet.
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Affiliation(s)
- Ayumi Kanno
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Shun-Ichiro Asahara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Ayuko Furubayashi
- Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan
| | - Katsuhisa Masuda
- Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan
| | - Risa Yoshitomi
- Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan
| | - Emi Suzuki
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Tomoko Takai
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | | | - Tomokazu Matsuda
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Alberto Bartolome
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York, USA
| | - Yushi Hirota
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Norihide Yokoi
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuka Inaba
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroshi Inoue
- Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Michihiro Matsumoto
- Department of Molecular Metabolic Regulation, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | | | - Takaya Abe
- Laboratory for Animal Resource Development and.,Laboratory for Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Fan-Yan Wei
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kazuhito Tomizawa
- Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and
| | - Susumu Seino
- Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Masato Kasuga
- National Center for Global Health and Medicine, Tokyo, Japan
| | - Yoshiaki Kido
- Division of Diabetes and Endocrinology, Department of Internal Medicine, and.,Division of Metabolism and Disease, Department of Biophysics, Kobe University Graduate School of Health Science, Kobe, Japan
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30
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Zeng Y, Zhang H, Tsao R, Mine Y. Lactobacillus pentosus S-PT84 Prevents Low-Grade Chronic Inflammation-Associated Metabolic Disorders in a Lipopolysaccharide and High-Fat Diet C57/BL6J Mouse Model. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2020; 68:4374-4386. [PMID: 32250610 DOI: 10.1021/acs.jafc.0c00118] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
A long-term exposure to lipopolysaccharides results in the gut inflammation and its impaired barrier function, leading to the development of metabolic disorders. In this study, the role of dietary heat killed Lactobacillus pentosus S-PT84 on preventing endotoxemia to maintain metabolic homeostasis was studied. We demonstrated that the treatment of L. pentosus S-PT84 improved the gut integrity by maintaining tight-junction protein expression, in order to suppress the infiltration of endotoxin into plasma. The systemic inflammatory responses were inhibited via reducing the secretion of TNF-α and MCP-1. Furthermore, the blood lipid profile and glucose level as well as adiponectin in both plasma and white adipose tissues (WAT) were preserved by L. pentosus S-PT84 through upregulation of PPAR-γ and IRS-1 expression in WAT. The above findings suggest that the metabolic homeostasis in mice treated with HFD and LPS was sustained by L. pentosus S-PT84, leading to reducing the early risk for progression into metabolic disorders.
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Affiliation(s)
- Yuhan Zeng
- Department of Food Science, University of Guelph, Guelph, Ontario N1G2W1, Canada
| | - Hua Zhang
- Department of Food Science, University of Guelph, Guelph, Ontario N1G2W1, Canada
- Department of Food Nutrition and Safety, College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
| | - Rong Tsao
- Guelph Food Research and Development Centre, Agriculture and Agri-Food Canada, 93 Stone Road West, Guelph, Ontario N1G 5C9, Canada
| | - Yoshinori Mine
- Department of Food Science, University of Guelph, Guelph, Ontario N1G2W1, Canada
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31
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Jara MA, Werneck-De-Castro JP, Lubaczeuski C, Johnson JD, Bernal-Mizrachi E. Pancreatic and duodenal homeobox-1 (PDX1) contributes to β-cell mass expansion and proliferation induced by Akt/PKB pathway. Islets 2020; 12:32-40. [PMID: 32876522 PMCID: PMC7527019 DOI: 10.1080/19382014.2020.1762471] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Maintenance of pancreatic β-cell mass and function is fundamental to glucose homeostasis and to prevent diabetes. The PI3 K-Akt-mTORC1 pathway is critical for β-cells mass and function, while PDX1 has been implicated in β-cell development, maturation, and function. Here we tested whether Akt signaling requires PDX1 expression to regulate β-cell mass, proliferation, and glucose homeostasis. In order to address that, we crossed a mouse model overexpressing constitutively active Akt mutant in β-cells (β-caAkt) with mice lacking one allele of PDX1gene (β-caAkt/pdx1+/-). While the β-caAkt mice exhibit higher plasma insulin levels, greater β-cell mass and improved glucose tolerance compared to control mice, the β-caAkt/pdx1+/- mice are hyperglycemic and intolerant to glucose. The changes in glucose homeostasis in β-caAkt/pdx1+/- were associated with a 60% reduction in β-cell mass compared to β-caAkt mice. The impaired β-cell mass in the β-caAkt/pdx1+/- mice can be explained by a lesser β-cell proliferation measured by the number of Ki67 positive β-cells. We did not observe any differences in apoptosis between β-caAkt/pdx1+/- and β-caAkt mice. In conclusion, PDX1 contributes to β-cell mass expansion and glucose metabolism induced by activation of Akt signaling.
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Affiliation(s)
- Mark Anthony Jara
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Joao Pedro Werneck-De-Castro
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
- Miami VA Health Care System, Miami, FL, USA
| | - Camila Lubaczeuski
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - James D. Johnson
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada
| | - Ernesto Bernal-Mizrachi
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, FL, USA
- Miami VA Health Care System, Miami, FL, USA
- CONTACT Ernesto Bernal-Mizrachi Department Of Internal Medicine, Division Of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, FL33136, USA
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32
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Ali G, Elsayed AK, Nandakumar M, Bashir M, Younis I, Abu Aqel Y, Memon B, Temanni R, Abubaker F, Taheri S, Abdelalim EM. Keratinocytes Derived from Patient-Specific Induced Pluripotent Stem Cells Recapitulate the Genetic Signature of Psoriasis Disease. Stem Cells Dev 2020; 29:383-400. [PMID: 31996098 PMCID: PMC7153648 DOI: 10.1089/scd.2019.0150] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Psoriasis is characterized by hyperproliferation and defective differentiation of keratinocytes (KCs). Patients with psoriasis are at a high risk of developing diabetes and cardiovascular diseases. The debate on the genetic origin of psoriasis pathogenesis remains unresolved due to lack of suitable in vitro human models mimicking the disease phenotypes. In this study, we provide the first human induced pluripotent stem cell (iPSC) model for psoriasis carrying the genetic signature of the patients. iPSCs were generated from patients with psoriasis (PsO-iPSCs) and healthy donors (Ctr-iPSCs) and were efficiently differentiated into mature KCs. RNA sequencing of KCs derived from Ctr-iPSCs and PsO-iPSCs identified 361 commonly upregulated and 412 commonly downregulated genes. KCs derived from PsO-iPSCs showed dysregulated transcripts associated with psoriasis and KC differentiation, such as HLA-C, KLF4, chemokines, type I interferon-inducible genes, solute carrier family, IVL, DSG1, and HLA-DQA1, as well as transcripts associated with insulin resistance, such as IRS2, GDF15, GLUT10, and GLUT14. Our data suggest that the KC abnormalities are the main driver triggering psoriasis pathology and highlights the substantial contribution of genetic predisposition in the development of psoriasis and insulin resistance.
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Affiliation(s)
- Gowher Ali
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Ahmed K Elsayed
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Manjula Nandakumar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar
| | - Mohammed Bashir
- Department of Endocrinology, Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ihab Younis
- Biological Sciences Program, Carnegie Mellon University in Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Yasmin Abu Aqel
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
| | - Bushra Memon
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
| | - Ramzi Temanni
- Biomedical Informatics Division, Sidra Medicine, Doha, Qatar
| | - Fadhil Abubaker
- Computer Sciences Program, Carnegie Mellon University in Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Shahrad Taheri
- Department of Medicine and Clinical Research Core, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha, Qatar.,College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Education City, Doha, Qatar
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Li Y, Wang K, Zhang P, Huang J, Liu Y, Wang Z, Lu Y, Tan S, Yang F, Tan Y. Pyrosequencing analysis of IRS1 methylation levels in schizophrenia with tardive dyskinesia. Mol Med Rep 2020; 21:1702-1708. [PMID: 32319643 PMCID: PMC7057828 DOI: 10.3892/mmr.2020.10984] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 01/17/2020] [Indexed: 12/16/2022] Open
Abstract
Tardive dyskinesia (TD) is a serious side effect of certain antipsychotic medications that are used to treat schizophrenia (SCZ) and other mental illnesses. The methylation status of the insulin receptor substrate 1 (IRS1) gene is reportedly associated with SCZ; however, no study, to the best of the authors' knowledge, has focused on the quantitative DNA methylation levels of the IRS1 gene using pyrosequencing in SCZ with or without TD. The present study aimed to quantify DNA methylation levels of 4 CpG sites in the IRS1 gene using a Chinese sample including SCZ patients with TD and without TD (NTD) and healthy controls (HCs). The general linear model (GLM) was used to detect DNA methylation levels among the 3 proposed groups (TD vs. NTD vs. HC). Mean DNA methylation levels of 4 CpG sites demonstrated normal distribution. Pearson's correlation analysis did not reveal any significant correlations between the DNA methylation levels of the 4 CpG sites and the severity of SCZ. GLM revealed significant differences between the 3 groups for CpG site 1 and the average of the 4 CpG sites (P=0.0001 and P=0.0126, respectively). Furthermore, the TD, NTD and TD + NTD groups demonstrated lower methylation levels in CpG site 1 (P=0.0003, P<0.0001 and P<0.0001, respectively) and the average of 4 CpG sites (P=0.0176, P=0.0063 and P=0.003, respectively) compared with the HC group. The results revealed that both NTD and TD patients had significantly decreased DNA methylation levels compared with healthy controls, which indicated a significant association between the DNA methylation levels of the IRS1 gene with SCZ and TD.
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Affiliation(s)
- Yanli Li
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Kesheng Wang
- Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, WV 26506, USA
| | - Ping Zhang
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Junchao Huang
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Ying Liu
- Department of Biostatistics and Epidemiology, College of Public Health, East Tennessee State University, Johnson City, TN 37614, USA
| | - Zhiren Wang
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Yongke Lu
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA
| | - Shuping Tan
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Fude Yang
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
| | - Yunlong Tan
- Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing 100096, P.R. China
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34
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Zhao Y, Tran M, Wang L, Shin DJ, Wu J. PDK4-Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice. Hepatol Commun 2020; 4:504-517. [PMID: 32258946 PMCID: PMC7109344 DOI: 10.1002/hep4.1484] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/10/2020] [Indexed: 12/29/2022] Open
Abstract
Liver regeneration requires intrahepatic and extrahepatic metabolic reprogramming to meet the high hepatic bioenergy demand for liver cell repopulation. This study aims to elucidate how pyruvate dehydrogenase kinase 4 (PDK4), a critical regulator of glucose and lipid metabolism, coordinates metabolic regulation with efficient liver growth. We found that hepatic Pdk4 expression was elevated after two-thirds partial hepatectomy (PHx). In Pdk4 -/- PHx mice, the liver/body weight ratio was more rapidly restored, accompanied by more aggressive hepatic DNA replication; however, Pdk4 -/- mice developed more severe hypoglycemia. In Pdk4 -/- PHx livers, the pro-regenerative insulin signaling was potentiated, as demonstrated by early peaking of the phosphorylation of insulin receptor, more remarkable induction of the insulin receptor substrate proteins, IRS1 and IRS2, and more striking activation of Akt. The hepatic up-regulation of CD36 contributed to the enhanced transient regeneration-associated steatosis in Pdk4 -/- PHx mice. Notably, CD36 overexpression in mice promoted the recovery of liver/body weight ratio and elevated intrahepatic adenosine triphosphate after PHx. CD36 expression was transcriptionally suppressed by FOXO1 (forkhead box protein O1), which was stabilized and translocated to the nucleus following AMPK (adenosine monophosphate-activated protein kinase) activation. PHx remarkably induced AMPK activation, which became incompetent to respond in Pdk4 -/- livers. Moreover, we defined that PDK4-regulated AMPK activation directly depended on intracellular adenosine monophosphate in vitro and in regenerative livers. Conclusion: PDK4 inhibition reprograms glucose and lipid metabolism to promote liver regeneration by enhancing hepatic insulin/Akt signaling and activating an AMPK/FOXO1/CD36 regulatory axis of lipid. These findings may lead to potential therapeutic strategies to prevent hepatic insufficiency and liver failure.
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Affiliation(s)
- Yulan Zhao
- Department of Physiology & Neurobiology University of Connecticut Storrs CT
| | - Melanie Tran
- Department of Physiology & Neurobiology University of Connecticut Storrs CT
| | - Li Wang
- Department of Internal Medicine Section of Digestive Diseases Yale University New Haven CT
| | - Dong-Ju Shin
- Department of Physiology & Neurobiology University of Connecticut Storrs CT
| | - Jianguo Wu
- Department of Physiology & Neurobiology University of Connecticut Storrs CT
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35
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Wu HK, Zhang Y, Cao CM, Hu X, Fang M, Yao Y, Jin L, Chen G, Jiang P, Zhang S, Song R, Peng W, Liu F, Guo J, Tang L, He Y, Shan D, Huang J, Zhou Z, Wang DW, Lv F, Xiao RP. Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis. Circulation 2019; 139:901-914. [PMID: 30586741 DOI: 10.1161/circulationaha.118.037216] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
BACKGROUND Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis. METHODS Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays. RESULTS Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker. CONCLUSIONS Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.
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Affiliation(s)
- Hong-Kun Wu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Yan Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Chun-Mei Cao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Xinli Hu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Meng Fang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Yuan Yao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Li Jin
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Gengjia Chen
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Peng Jiang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Shuo Zhang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Ruisheng Song
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Wei Peng
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Fenghua Liu
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Jiaojiao Guo
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Lifei Tang
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Yanyun He
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Dan Shan
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Jin Huang
- Department of Internal Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China (J.H., D.W.)
| | - Zhuan Zhou
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.).,Beijing City Key Laboratory of Cardiometabolic Molecular Medicine (Z.Z., R.-P.X.).,Peking University, China. Peking-Tsinghua Center for Life Sciences, Beijing, China (Z.Z., R.-P.X.)
| | - Dao Wen Wang
- Department of Internal Medicine, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China (J.H., D.W.)
| | - Fengxiang Lv
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.)
| | - Rui-Ping Xiao
- State Key Laboratory of Membrane Biology, Institute of Molecular Medicine (H.-K.W., Y.Z., C.-M.C., X.H., M.F., Y.Y., L.J., G.C., P.J., S.Z., R.S., W.P., F.L., J.G., L.T., Y.H., D.S., Z.Z., F.L., R.-P.X.).,Beijing City Key Laboratory of Cardiometabolic Molecular Medicine (Z.Z., R.-P.X.).,Peking University, China. Peking-Tsinghua Center for Life Sciences, Beijing, China (Z.Z., R.-P.X.)
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Nogueira-Lima E, Lamas CDA, Baseggio AM, do Vale JSF, Maróstica Junior MR, Cagnon VHA. High-fat diet effects on the prostatic adenocarcinoma model and jaboticaba peel extract intake: protective response in metabolic disorders and liver histopathology. Nutr Cancer 2019; 72:1366-1377. [DOI: 10.1080/01635581.2019.1684526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Ellen Nogueira-Lima
- Department of Structural and Functional Biology, University of Campinas, São Paulo, Brazil
| | | | - Andressa Mara Baseggio
- Department of Structural and Functional Biology, University of Campinas, São Paulo, Brazil
- Department of Food and Nutrition, University of Campinas, São Paulo, Brazil
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37
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Hasannejad M, Samsamshariat SZ, Esmaili A, Jahanian-Najafabadi A. Klotho induces insulin resistance possibly through interference with GLUT4 translocation and activation of Akt, GSK3β, and PFKfβ3 in 3T3-L1 adipocyte cells. Res Pharm Sci 2019; 14:369-377. [PMID: 31516514 PMCID: PMC6714116 DOI: 10.4103/1735-5362.263627] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Klotho is considered as an anti-aging factor inducing insulin resistance and involved in type 2 diabetes. However, mechanisms by which klotho induces insulin resistance remain to be understood. Thus, in this study, we aimed to evaluate possible interference points of klotho with insulin signaling pathways in 3T3-L1 adipocyte cells by focusing on phosphorylation levels of Akt, GSK3β, PFK-fβ3, and GLUT4 translocation. Differentiation of 3T3-L1 cells to the adipocyte-like cells were performed using specific differentiation kit and confirmed by mRNA expression assay of PPARγ using qRT-PCR, and Sudan black staining of lipid droplets. Then cells were co-treated with klotho and insulin. Expression and translocation of GLUT4 mRNA were evaluated using qRT-PCR and Alexa flour 488 conjugated GLUT4 antibody, respectively. P-Akt/Akt, p-GSK3β/GSK3β, and p-PFKfβ3/PFKfβ3 ratios were determined in insulin and klotho/insulin treated cells using western blot. Our result indicated that GLUT4 expression were decreased to 0.72 ± 0.16 fold in insulin treated cells, however it was calculated 1.12 ± 0.25 fold in klotho/insulin treated cells. In addition, klotho prevented GLUT4 membrane translocation by 27.2% in comparison with insulin-treated cells (P < 0.05). Interestingly, in insulin/klotho co-treated cells, phospho-levels of Akt, GSK3β, and PFKfβ3 proteins was decreased to 2.34 ± 0.14, 2.29 ± 0.63, and 1.95 ± 0.37 fold in comparison with the insulin cells, (P < 0.05). In conclusion, our study indicated that klotho induces insulin resistance in adipocytes possibly through prevention of GLUT4 translocation, and interfere with phosphorylation of Akt, GSK3β, and PFKf3β intracellular signaling mediators by insulin.
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Affiliation(s)
- Mohamad Hasannejad
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Seyed Ziaaldin Samsamshariat
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Armita Esmaili
- Department of Pathology, Mehrgan hospital, Kerman University of Medical Sciences and Health services, Kerman, I.R. Iran
| | - Ali Jahanian-Najafabadi
- Department of Pharmaceutical Biotechnology, Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
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38
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Abdul Razzak R, Florence GJ, Gunn-Moore FJ. Approaches to CNS Drug Delivery with a Focus on Transporter-Mediated Transcytosis. Int J Mol Sci 2019; 20:E3108. [PMID: 31242683 PMCID: PMC6627589 DOI: 10.3390/ijms20123108] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/15/2019] [Accepted: 06/16/2019] [Indexed: 12/13/2022] Open
Abstract
Drug delivery to the central nervous system (CNS) conferred by brain barriers is a major obstacle in the development of effective neurotherapeutics. In this review, a classification of current approaches of clinical or investigational importance for the delivery of therapeutics to the CNS is presented. This classification includes the use of formulations administered systemically that can elicit transcytosis-mediated transport by interacting with transporters expressed by transvascular endothelial cells. Neurotherapeutics can also be delivered to the CNS by means of surgical intervention using specialized catheters or implantable reservoirs. Strategies for delivering drugs to the CNS have evolved tremendously during the last two decades, yet, some factors can affect the quality of data generated in preclinical investigation, which can hamper the extension of the applications of these strategies into clinically useful tools. Here, we disclose some of these factors and propose some solutions that may prove valuable at bridging the gap between preclinical findings and clinical trials.
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Affiliation(s)
- Rana Abdul Razzak
- Medical and Biological Sciences Building, School of Biology, University of St Andrews, St Andrews KY16 9TF, UK.
- Biomedical Science Research Centre, Schools of Chemistry and Biology, University of St Andrews, St Andrews KY16 9TF, UK.
| | - Gordon J Florence
- Biomedical Science Research Centre, Schools of Chemistry and Biology, University of St Andrews, St Andrews KY16 9TF, UK.
| | - Frank J Gunn-Moore
- Medical and Biological Sciences Building, School of Biology, University of St Andrews, St Andrews KY16 9TF, UK.
- Biomedical Science Research Centre, Schools of Chemistry and Biology, University of St Andrews, St Andrews KY16 9TF, UK.
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39
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Li J, Bai L, Wei F, Zhao J, Wang D, Xiao Y, Yan W, Wei J. Therapeutic Mechanisms of Herbal Medicines Against Insulin Resistance: A Review. Front Pharmacol 2019; 10:661. [PMID: 31258478 PMCID: PMC6587894 DOI: 10.3389/fphar.2019.00661] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 05/23/2019] [Indexed: 12/16/2022] Open
Abstract
Insulin resistance is a condition in which insulin sensitivity is reduced and the insulin signaling pathway is impaired. Although often expressed as an increase in insulin concentration, the disease is characterized by a decrease in insulin action. This increased workload of the pancreas and the consequent decompensation are not only the main mechanisms for the development of type 2 diabetes (T2D), but also exacerbate the damage of metabolic diseases, including obesity, nonalcoholic fatty liver disease, polycystic ovary syndrome, metabolic syndrome, and others. Many clinical trials have suggested the potential role of herbs in the treatment of insulin resistance, although most of the clinical trials included in this review have certain flaws and bias risks in their methodological design, including the generation of randomization, the concealment of allocation, blinding, and inadequate reporting of sample size estimates. These studies involve not only the single-flavored herbs, but also herbal formulas, extracts, and active ingredients. Numerous of in vitro and in vivo studies have pointed out that the role of herbal medicine in improving insulin resistance is related to interventions in various aspects of the insulin signaling pathway. The targets involved in these studies include insulin receptor substrate, phosphatidylinositol 3-kinase, glucose transporter, AMP-activated protein kinase, glycogen synthase kinase 3, mitogen-activated protein kinases, c-Jun-N-terminal kinase, nuclear factor-kappaB, protein tyrosine phosphatase 1B, nuclear factor-E2-related factor 2, and peroxisome proliferator-activated receptors. Improved insulin sensitivity upon treatment with herbal medicine provides considerable prospects for treating insulin resistance. This article reviews studies of the target mechanisms of herbal treatments for insulin resistance.
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Affiliation(s)
- Jun Li
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Litao Bai
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fan Wei
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jing Zhao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Danwei Wang
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yao Xiao
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weitian Yan
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Wei
- Department of Endocrinology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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40
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Zhou J, Ho CT, Long P, Meng Q, Zhang L, Wan X. Preventive Efficiency of Green Tea and Its Components on Nonalcoholic Fatty Liver Disease. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2019; 67:5306-5317. [PMID: 30892882 DOI: 10.1021/acs.jafc.8b05032] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a typical chronic liver disease highly correlated with metabolic syndrome. Growing prevalence of NAFLD is supposed to be linked with the unhealthy lifestyle, especially high-calorie diet and lacking enough exercise. Currently, there is no validated pharmacological therapy for NAFLD except for weight reduction. However, many dietary strategies had preventive effects on the development of liver steatosis or its progression. As one of the most common beverages, green tea contains abundant bioactive compounds possessing antioxidant, lipid-lowering, and anti-inflammatory effects, as well as improving insulin resistance and gut dysbiosis that can alleviate the risk of NAFLD. Hence, in this review, we summarized the studies of green tea and its components on NAFLD from animal experiments and human interventions and discussed the potential mechanisms. Available evidence suggested that tea consumption is promising to prevent NAFLD, and further mechanisms and clinical studies need to be investigated.
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Affiliation(s)
| | - Chi-Tang Ho
- Department of Food Science , Rutgers University , New Brunswick , New Jersey , United States
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Afaq S, Kooner AS, Loh M, Kooner JS, Chambers JC. Contribution of lower physical activity levels to higher risk of insulin resistance and associated metabolic disturbances in South Asians compared to Europeans. PLoS One 2019; 14:e0216354. [PMID: 31063476 PMCID: PMC6504088 DOI: 10.1371/journal.pone.0216354] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Accepted: 04/18/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Insulin resistance and related metabolic disturbances are major risk factors for the higher T2D risk and associated morbidity and mortality amongst South Asians. The contribution of physical activity to the increased prevalence of insulin resistance and related disturbances amongst South Asians is unknown. METHODS We recruited 902 South Asian and European men and women, aged 35-85 years from the ongoing LOLIPOP study. Clinical characterisation comprised standardised questionnaire and measurement of height, weight, waist and hip circumference and blood pressure. Fasting bloods were taken for assessment of glucose, insulin, lipids and HbA1c. Physical activity was quantified using a validated accelerometer, Actigraph GT3X+, worn for 7 days. Univariate and multivariate approaches were used to investigate the relationship between ethnicity, physical activity, insulin resistance and related metabolic disturbances. RESULTS Total physical activity was ~31% (P = 0.01) lower amongst South Asians compared to Europeans (Mean MET.minutes [SD]: 1505.2 [52] vs. 2050.9 [86.6], P<0.001). After adjusting for age and sex, total physical activity had a negative association with HOMA-IR (B [SE]: -0.18 [0.08], P = 0.04) and fasting glucose levels (B[SE]: -0.11 [0.04], P = 0.02). There was no association between physical activity and other glycemic and lipid parameters. Total physical activity per week contributed towards the differences in insulin resistance and associated metabolic disturbances between South Asians and Europeans. CONCLUSION Lower levels of physical activity may contribute to the increased insulin resistance in South Asians compared to Europeans. Our results suggest that lifestyle modification through increased physical activity may help to improve glucose metabolism and reduce the burden of excess T2D and related complications amongst South Asians.
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Affiliation(s)
- Saima Afaq
- Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom
- Institute of Public health and Social Sciences, Khyber medical university, Peshawar, Pakistan
- * E-mail: ,
| | - Angad S. Kooner
- Hillingdon hospital, NHS Trust, Hillingdon, Greater London, United Kingdom
| | - Marie Loh
- Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom
| | - Jaspal S. Kooner
- Hammersmith Hospital, London, United Kingdom
- Ealing Hospital, Southall, Middlesex, United Kingdom
- NHLI, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - John C. Chambers
- Epidemiology and Biostatistics, Imperial College London, Norfolk Place, London, United Kingdom
- Hammersmith Hospital, London, United Kingdom
- Ealing Hospital, Southall, Middlesex, United Kingdom
- MRC-HPA Centre for Environment and Health, Imperial College London, Norfolk Place, London, United Kingdom
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Abstract
PURPOSE OF REVIEW The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health. RECENT FINDINGS Generation of multi-omic data to measure each of the "biologic layers," developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become a routine in clinical and public health, additional large-scale multi-omic initiatives are needed along with better assessment of our environment to delineate an individual's diabetes subtype for improved detection and management.
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Affiliation(s)
- Yuan Lin
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA
| | - Jennifer Wessel
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA.
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
- Diabetes Translational Research Center, Indiana University School of Medicine, Indianapolis, IN, USA.
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Veeraragavulu P, Yellapu NK, Yerrathota S, Adi PJ, Matcha B. Three Novel Mutations I65S, R66S, and G86R Divulge Significant Conformational Variations in the PTB Domain of the IRS1 Gene. ACS OMEGA 2019; 4:2217-2224. [PMID: 31660472 PMCID: PMC6814177 DOI: 10.1021/acsomega.8b01712] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 09/25/2018] [Indexed: 06/10/2023]
Abstract
Insulin receptor substrate 1 (IRS1) is one of the major substrates for the IR, and their interaction mediates several downstream insulin signaling pathways. In this study, we have identified three novel mutations in the IRS1 gene of type 2 diabetic (T2D) patients, which reflected in the amino acid changes as I65S, R66S, and G86R in the phosphotyrosine binding domain of the IRS1 protein. The impact of these mutations on the structure and function of the IRS1 protein was evaluated through molecular modeling studies, and distinct conformational fluctuations were recorded. The variable binding affinities and positional displacement of these mutant models were observed in the ligand-binding cleft of IR. The mutant IRS1 models triggered conformational changes in the L1 domain of IR upon their binding. Such structural variations in IRS1 and IR structures due to mutations resulted in variable molecular interactions that could lead to altered insulin transduction, followed by insulin resistance and T2D.
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Affiliation(s)
| | - Nanda Kumar Yellapu
- Division
of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati 517502, India
| | - Sireesha Yerrathota
- Division
of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati 517502, India
| | - Pradeepkiran Jangampalli Adi
- Division
of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati 517502, India
- Garrison
Institute on Aging, Texas Tech University
Health Sciences Center, 3601 4th Street, MS 9424, Lubbock, Texas 79430, United
States
| | - Bhaskar Matcha
- Division
of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati 517502, India
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44
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Nakazawa H, Ikeda K, Shinozaki S, Yasuhara S, Yu YM, Martyn JAJ, Tompkins RG, Yorozu T, Inoue S, Kaneki M. Coenzyme Q10 protects against burn-induced mitochondrial dysfunction and impaired insulin signaling in mouse skeletal muscle. FEBS Open Bio 2019; 9:348-363. [PMID: 30761259 PMCID: PMC6356165 DOI: 10.1002/2211-5463.12580] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Revised: 12/13/2018] [Accepted: 12/14/2018] [Indexed: 12/29/2022] Open
Abstract
Mitochondrial dysfunction is associated with metabolic alterations in various disease states, including major trauma (e.g., burn injury). Metabolic derangements, including muscle insulin resistance and hyperlactatemia, are a clinically significant complication of major trauma. Coenzyme Q10 (CoQ10) is an essential cofactor for mitochondrial electron transport, and its reduced form acts as a lipophilic antioxidant. Here, we report that burn injury induces impaired muscle insulin signaling, hyperlactatemia, mitochondrial dysfunction (as indicated by suppressed mitochondrial oxygen consumption rates), morphological alterations of the mitochondria (e. g., enlargement, and loss of cristae structure), mitochondrial oxidative stress, and disruption of mitochondrial integrity (as reflected by increased mitochondrial DNA levels in the cytosol and circulation). All of these alterations were significantly alleviated by CoQ10 treatment compared with vehicle alone. These findings indicate that CoQ10 treatment is efficacious in protecting against mitochondrial dysfunction and insulin resistance in skeletal muscle of burned mice. Our data highlight CoQ10 as a potential new strategy to prevent mitochondrial damage and metabolic dysfunction in burn patients.
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Affiliation(s)
- Harumasa Nakazawa
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Medical School Charlestown MA USA.,Shriners Hospitals for Children Boston MA USA.,Department of Anesthesiology Kyorin University School of Medicine Tokyo Japan
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction Research Center for Genomic Medicine Saitama Medical University Japan
| | - Shohei Shinozaki
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Medical School Charlestown MA USA.,Shriners Hospitals for Children Boston MA USA.,Department of Life Sciences and Bioethics Tokyo Medical and Dental University Japan
| | - Shingo Yasuhara
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Medical School Charlestown MA USA.,Shriners Hospitals for Children Boston MA USA
| | - Yong-Ming Yu
- Shriners Hospitals for Children Boston MA USA.,Department of Surgery Massachusetts General Hospital Harvard Medical School Boston MA USA
| | - J A Jeevendra Martyn
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Medical School Charlestown MA USA.,Shriners Hospitals for Children Boston MA USA
| | - Ronald G Tompkins
- Shriners Hospitals for Children Boston MA USA.,Department of Surgery Massachusetts General Hospital Harvard Medical School Boston MA USA
| | - Tomoko Yorozu
- Department of Anesthesiology Kyorin University School of Medicine Tokyo Japan
| | - Satoshi Inoue
- Division of Gene Regulation and Signal Transduction Research Center for Genomic Medicine Saitama Medical University Japan.,Tokyo Metropolitan Institute of Gerontology Japan
| | - Masao Kaneki
- Department of Anesthesia, Critical Care and Pain Medicine Massachusetts General Hospital Harvard Medical School Charlestown MA USA.,Shriners Hospitals for Children Boston MA USA
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45
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Development of insulin resistance in Nischarin mutant female mice. Int J Obes (Lond) 2018; 43:1046-1057. [PMID: 30546133 DOI: 10.1038/s41366-018-0241-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 06/18/2018] [Accepted: 09/16/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND/OBJECTIVES NISCH-STAB1 is a newly identified locus correlated to human waist-hip ratio (WHR), which is a risk indicator of developing obesity-associated diabetes. Our previous studies have shown that Nisch mutant male mice increased glucose tolerance in chow-fed conditions. Thus we hypothesized that Nisch mutant mice will have changes in insulin resistance, adipocytes, hepatic steatosis when mice are fed with high-fat diet (HFD). METHODS Insulin resistance was assessed in Nisch mutant mice and WT mice fed with high-fat diet (60% by kCal) or chow diet. Whole-body energy metabolism was examined using an indirect calorimeter. Adipose depots including inguinal white adipose tissue (WAT), perigonadal WAT, retroperitoneal WAT, and mesenteric WAT were extracted. Area and eqdiameter of each adipocyte were determined, and insulin signaling was examined as well. Paired samples of subcutaneous and omental visceral adipose tissue were obtained from 400 individuals (267 women, 133 men), and examined the expression of Nischarin. RESULTS We found that insulin signaling was impaired in major insulin-sensitive tissues of Nisch mutant female mice. When mice were fed with HFD for 15 weeks, the Nisch mutant female mice not only developed severe insulin resistance and decreased glucose tolerance compared with wild-type control mice, but also accumulated more white fat, had larger adipocytes and developed severe hepatic steatosis than wild-type control mice. To link our animal studies to human diseases, we further analyzed Nischarin expression in the paired human samples of visceral and subcutaneous adipose tissue from Caucasians. In humans, we found that Nischarin expression is attenuated in adipose tissue with obesity. More importantly, we found that Nischarin mRNA inversely correlated with parameters of obesity, fat distribution, lipid and glucose metabolism. CONCLUSIONS Taken together, our data revealed sexual dimorphism of Nischarin in body fat distribution, insulin resistance, and glucose tolerance in mice.
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46
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Gilani A, Pandey V, Garcia V, Agostinucci K, Singh SP, Schragenheim J, Bellner L, Falck JR, Paudyal MP, Capdevila JH, Abraham NG, Laniado Schwartzman M. High-fat diet-induced obesity and insulin resistance in CYP4a14 -/- mice is mediated by 20-HETE. Am J Physiol Regul Integr Comp Physiol 2018; 315:R934-R944. [PMID: 30088983 PMCID: PMC6295494 DOI: 10.1152/ajpregu.00125.2018] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 07/20/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023]
Abstract
20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to positively correlate with body mass index, hyperglycemia, and plasma insulin levels. This study seeks to identify a causal relationship between 20-HETE and obesity-driven insulin resistance. Cyp4a14-/- male mice, a model of 20-HETE overproduction, were fed a regular or high-fat diet (HFD) for 15 wk. 20-SOLA [2,5,8,11,14,17-hexaoxanonadecan-19-yl 20-hydroxyeicosa-6( Z),15( Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed mice gained significant weight (16.7 ± 3.2 vs. 3.8 ± 0.35 g, P < 0.05) and developed hyperglycemia (157 ± 3 vs. 121 ± 7 mg/dl, P < 0.05) and hyperinsulinemia (2.3 ± 0.4 vs. 0.5 ± 0.1 ng/ml, P < 0.05) compared with regular diet-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 ± 1 vs. 16.7 ± 3 g, P < 0.05) and normalized the hyperglycemia (157 ± 7 vs. 102 ± 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 ± 0.1 vs. 2.3 ± 0.4 ng/ml, P < 0.05). The impaired glucose homeostasis and insulin resistance in HFD-fed mice evidenced by reduced insulin and glucose tolerance were also ameliorated by 20-SOLA. Circulatory and adipose tissue 20-HETE levels significantly increased in HFD-fed mice correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, insulin resistance, and impaired insulin signaling.
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Affiliation(s)
- Ankit Gilani
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Varunkumar Pandey
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Victor Garcia
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Kevin Agostinucci
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Shailendra P Singh
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Joseph Schragenheim
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - Lars Bellner
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
| | - John R Falck
- Department of Biochemistry, University of Texas Southwestern Medical Center, Texas
| | - Mahesh P Paudyal
- Department of Biochemistry, University of Texas Southwestern Medical Center, Texas
| | - Jorge H Capdevila
- Department of Medicine, Vanderbilt University Medical Center , Nashville, Tennessee
| | - Nader G Abraham
- Departments of Pharmacology, New York Medical College School of Medicine, Valhalla, New York
- Department of Medicine, New York Medical College School of Medicine, Valhalla, New York
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47
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Lee Y, Kwon EY, Choi MS. Dietary Isoliquiritigenin at a Low Dose Ameliorates Insulin Resistance and NAFLD in Diet-Induced Obesity in C57BL/6J Mice. Int J Mol Sci 2018; 19:ijms19103281. [PMID: 30360437 PMCID: PMC6214092 DOI: 10.3390/ijms19103281] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 10/13/2018] [Accepted: 10/18/2018] [Indexed: 02/08/2023] Open
Abstract
Isoliquiritigenin (ILG) is a flavonoid constituent of Glycyrrhizae plants. The current study investigated the effects of ILG on diet-induced obesity and metabolic diseases. C57BL/6J mice were fed a normal diet (AIN-76 purified diet), high-fat diet (40 kcal% fat), and high-fat diet +0.02% (w/w) ILG for 16 weeks. Supplementation of ILG resulted in decreased body fat mass and plasma cholesterol level. ILG ameliorated hepatic steatosis by suppressing the expression of hepatic lipogenesis genes and hepatic triglyceride and fatty acid contents, while enhancing β-oxidation in the liver. ILG improved insulin resistance by lowering plasma glucose and insulin levels. This was also demonstrated by the intraperitoneal glucose tolerance test (IPGTT). Additionally, ILG upregulated the expression of insulin signaling-related genes in the liver and muscle. Interestingly, ILG elevated energy expenditure by increasing the expression of thermogenesis genes, which is linked to stimulated mitochondrial biogenesis and uncoupled cellular respiration in brown adipose tissue. ILG also suppressed proinflammatory cytokine levels in the plasma. These results suggest that ILG supplemented at 0.02% in the diet can ameliorate body fat mass, plasma cholesterol, non-alcoholic fatty liver disease, and insulin resistance; these effects were partly mediated by increasing energy expenditure in high-fat fed mice.
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Affiliation(s)
- Youngmi Lee
- Department of Food Science and Nutrition, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea.
| | - Eun-Young Kwon
- Department of Food Science and Nutrition, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea.
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea.
| | - Myung-Sook Choi
- Department of Food Science and Nutrition, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea.
- Center for Food and Nutritional Genomics Research, Kyungpook National University, 1370 San-Kyuk Dong Puk-Ku, Daegu 41566, Korea.
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48
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Honma M, Sawada S, Ueno Y, Murakami K, Yamada T, Gao J, Kodama S, Izumi T, Takahashi K, Tsukita S, Uno K, Imai J, Kakazu E, Kondo Y, Mizuno K, Kawagishi N, Shimosegawa T, Katagiri H. Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. Int J Obes (Lond) 2018; 42:1544-1555. [PMID: 29717275 PMCID: PMC6160396 DOI: 10.1038/s41366-018-0062-9] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 01/31/2018] [Accepted: 02/13/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND/OBJECTIVE Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.
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Affiliation(s)
- Midori Honma
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, CREST, Tokyo, Japan
| | - Keigo Murakami
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junhong Gao
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Sohei Tsukita
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | | | | | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Naoki Kawagishi
- Division of Transplantation, Reconstruction and Endoscopic Surgery, Tohoku University Hospital, Sendai, Japan
| | - Tooru Shimosegawa
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan.
- Japan Agency for Medical Research and Development, CREST, Tokyo, Japan.
- Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai, Japan.
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Shin J, Fukuhara A, Onodera T, Kita S, Yokoyama C, Otsuki M, Shimomura I. SDF-1 Is an Autocrine Insulin-Desensitizing Factor in Adipocytes. Diabetes 2018; 67:1068-1078. [PMID: 29581126 DOI: 10.2337/db17-0706] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 03/14/2018] [Indexed: 11/13/2022]
Abstract
Insulin desensitization occurs not only under the obese diabetic condition but also in the fasting state. However, little is known about the common secretory factor(s) that are regulated under these two insulin-desensitized conditions. Here, using database analysis and in vitro and in vivo experiments, we identified stromal derived factor-1 (SDF-1) as an insulin-desensitizing factor in adipocytes, overexpressed in both fasting and obese adipose tissues. Exogenously added SDF-1 induced extracellular signal-regulated kinase signal, which phosphorylated and degraded IRS-1 protein in adipocytes, decreasing insulin-mediated signaling and glucose uptake. In contrast, knockdown of endogenous SDF-1 or inhibition of its receptor in adipocytes markedly increased IRS-1 protein levels and enhanced insulin sensitivity, indicating the autocrine action of SDF-1. In agreement with these findings, adipocyte-specific ablation of SDF-1 enhanced insulin sensitivity in adipose tissues and in the whole body. These results point to a novel regulatory mechanism of insulin sensitivity mediated by adipose autocrine SDF-1 action and provide a new insight into the process of insulin desensitization in adipocytes.
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Affiliation(s)
- Jihoon Shin
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan
- Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Atsunori Fukuhara
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Toshiharu Onodera
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Adipose Management, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Chieko Yokoyama
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Department of Nutrition and Life Science, Kanagawa Institute of Technology, Atsugi, Kanagawa, Japan
| | - Michio Otsuki
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- Osaka University Graduate School of Frontier Biosciences, Suita, Osaka, Japan
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50
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New mechanistic insights on the metabolic-disruptor role of chlorpyrifos in apoE mice: a focus on insulin- and leptin-signalling pathways. Arch Toxicol 2018; 92:1717-1728. [DOI: 10.1007/s00204-018-2174-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 01/31/2018] [Indexed: 01/08/2023]
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