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Kim J, Oh CM, Kim H. The Interplay of Adipokines and Pancreatic Beta Cells in Metabolic Regulation and Diabetes. Biomedicines 2023; 11:2589. [PMID: 37761031 PMCID: PMC10526203 DOI: 10.3390/biomedicines11092589] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The interplay between adipokines and pancreatic beta cells, often referred to as the adipo-insular axis, plays a crucial role in regulating metabolic homeostasis. Adipokines are signaling molecules secreted by adipocytes that have profound effects on several physiological processes. Adipokines such as adiponectin, leptin, resistin, and visfatin influence the function of pancreatic beta cells. The reciprocal communication between adipocytes and beta cells is remarkable. Insulin secreted by beta cells affects adipose tissue metabolism, influencing lipid storage and lipolysis. Conversely, adipokines released from adipocytes can influence beta cell function and survival. Chronic obesity and insulin resistance can lead to the release of excess fatty acids and inflammatory molecules from the adipose tissue, contributing to beta cell dysfunction and apoptosis, which are key factors in developing type 2 diabetes. Understanding the complex interplay of the adipo-insular axis provides insights into the mechanisms underlying metabolic regulation and pathogenesis of metabolic disorders. By elucidating the molecular mediators involved in this interaction, new therapeutic targets and strategies may emerge to reduce the risk and progression of diseases, such as type 2 diabetes and its associated complications. This review summarizes the interactions between adipokines and pancreatic beta cells, and their roles in the pathogenesis of diabetes and metabolic diseases.
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Affiliation(s)
- Joon Kim
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea;
| | - Hyeongseok Kim
- Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 35105, Republic of Korea
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35105, Republic of Korea
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Bocian-Jastrzębska A, Malczewska-Herman A, Rosiek V, Kos-Kudła B. Assessment of the Role of Leptin and Adiponectinas Biomarkers in Pancreatic Neuroendocrine Neoplasms. Cancers (Basel) 2023; 15:3517. [PMID: 37444627 DOI: 10.3390/cancers15133517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/23/2023] [Accepted: 07/04/2023] [Indexed: 07/15/2023] Open
Abstract
Data on the possible connection between circulating adipokines and PanNENs are limited. This novel study aimed to assess the serum levels of leptin and adiponectin and their ratio in patients with PanNENs and to evaluate the possible relationship between them and PanNEN's grade or stage, including the presence of metastases. The study group consisted of PanNENs (n = 83), and healthy controls (n = 39). Leptin and adiponectin measurement by an ELISA assay was undertaken in the entire cohort. The serum concentration of adiponectin was significantly higher in the control group compared to the study group (p < 0.001). The concentration of leptin and adiponectin was significantly higher in females than in males (p < 0.01). Anincreased leptin-adiponectin ratio was observed in well-differentiated PanNENs (G1) vs. moderatelydifferentiated PanNENs (G2) (p < 0.05). An increased leptin-adiponectin ratio was found in PanNENs with Ki-67 < 3% vs. Ki-67 ≥ 3% (p < 0.05). PanNENs with distal disease presented lower leptin levels (p < 0.001) and a decreased leptin-adiponectin ratio (p < 0.01) compared with the localized disease group. Leptin, adiponectin, and the leptin-adiponectin ratio may serve as potential diagnostic, prognostic, and predictive biomarkers for PanNENs. Leptin levels and the leptin-adiponectin ratio may play an important role as predictors of malignancy and metastasis in PanNENs.
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Affiliation(s)
- Agnes Bocian-Jastrzębska
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Anna Malczewska-Herman
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Violetta Rosiek
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
| | - Beata Kos-Kudła
- Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinogy, Medical University of Silesia, 40-514 Katowice, Poland
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Function and regulation of phosphatase 1 in healthy and diseased heart. Cell Signal 2021; 90:110203. [PMID: 34822978 DOI: 10.1016/j.cellsig.2021.110203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 11/12/2021] [Accepted: 11/18/2021] [Indexed: 12/12/2022]
Abstract
Reversible phosphorylation of ion channels and calcium-handling proteins provides precise post-translational regulation of cardiac excitation and contractility. Serine/threonine phosphatases govern dephosphorylation of the majority of cardiac proteins. Accordingly, dysfunction of this regulation contributes to the development and progression of heart failure and atrial fibrillation. On the molecular level, these changes include alterations in the expression level and phosphorylation status of Ca2+ handling and excitation-contraction coupling proteins provoked by dysregulation of phosphatases. The serine/threonine protein phosphatase PP1 is one a major player in the regulation of cardiac excitation-contraction coupling. PP1 essentially impacts on cardiac physiology and pathophysiology via interactions with the cardiac ion channels Cav1.2, NKA, NCX and KCNQ1, sarcoplasmic reticulum-bound Ca2+ handling proteins such as RyR2, SERCA and PLB as well as the contractile proteins MLC2, TnI and MyBP-C. PP1 itself but also PP1-regulatory proteins like inhibitor-1, inhibitor-2 and heat-shock protein 20 are dysregulated in cardiac disease. Therefore, they represent interesting targets to gain more insights in heart pathophysiology and to identify new treatment strategies for patients with heart failure or atrial fibrillation. We describe the genetic and holoenzymatic structure of PP1 and review its role in the heart and cardiac disease. Finally, we highlight the importance of the PP1 regulatory proteins for disease manifestation, provide an overview of genetic models to study the role of PP1 for the development of heart failure and atrial fibrillation and discuss possibilities of pharmacological interventions.
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Henquin JC. Non-glucose modulators of insulin secretion in healthy humans: (dis)similarities between islet and in vivo studies. Metabolism 2021; 122:154821. [PMID: 34174327 DOI: 10.1016/j.metabol.2021.154821] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/10/2021] [Accepted: 06/18/2021] [Indexed: 12/17/2022]
Abstract
Optimal metabolic homeostasis requires precise temporal and quantitative control of insulin secretion. Both in vivo and in vitro studies have often focused on the regulation by glucose although many additional factors including other nutrients, neurotransmitters, hormones and drugs, modulate the secretory function of pancreatic β-cells. This review is based on the analysis of clinical investigations characterizing the effects of non-glucose modulators of insulin secretion in healthy subjects, and of experimental studies testing the same modulators in islets isolated from normal human donors. The aim was to determine whether the information gathered in vitro can reliably be translated to the in vivo situation. The comparison evidenced both convincing similarities and areas of discordance. The lack of coherence generally stems from the use of exceedingly high concentrations of test agents at too high or too low glucose concentrations in vitro, which casts doubts on the physiological relevance of a number of observations made in isolated islets. Future projects resorting to human islets should avoid extreme experimental conditions, such as oversized stimulations or inhibitions of β-cells, which are unlikely to throw light on normal insulin secretion and contribute to the elucidation of its defects.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium.
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Abstract
Leptin is a pluripotent peptide hormone produced mainly by adipocytes, as well as by other tissues such as the stomach. Leptin primarily acts on the central nervous system, particularly the hypothalamus, where this hormone regulates energy homeostasis and neuroendocrine function. Owing to this, disruption of leptin signaling has been linked with numerous pathological conditions. Recent studies have also highlighted the diverse roles of leptin in the digestive system including immune regulation, cell proliferation, tissue healing, and glucose metabolism. Of note, leptin acts differently under physiological and pathological conditions. Here, we review the current knowledge on the functions of leptin and its downstream signaling in the gastrointestinal tract and accessory digestive organs, with an emphasis on its physiological and pathological implications. We also discuss the current therapeutic uses of recombinant leptin, as well as its limitations.
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Affiliation(s)
- Min-Hyun Kim
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Hyeyoung Kim
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, Korea
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Benáková Š, Holendová B, Plecitá-Hlavatá L. Redox Homeostasis in Pancreatic β-Cells: From Development to Failure. Antioxidants (Basel) 2021; 10:antiox10040526. [PMID: 33801681 PMCID: PMC8065646 DOI: 10.3390/antiox10040526] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 12/16/2022] Open
Abstract
Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.
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Affiliation(s)
- Štěpánka Benáková
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- First Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Prague, Czech Republic
| | - Blanka Holendová
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology, Czech Academy of Sciences, 142 20 Prague 4, Czech Republic; (Š.B.); (B.H.)
- Department of Mitochondrial Physiology, Czech Academy of Sciences, Videnska 1083, 142 20 Prague 4, Czech Republic
- Correspondence: ; Tel.: +420-296-442-285
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Prenatal Choline Supplementation during High-Fat Feeding Improves Long-Term Blood Glucose Control in Male Mouse Offspring. Nutrients 2020; 12:nu12010144. [PMID: 31947955 PMCID: PMC7019888 DOI: 10.3390/nu12010144] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 12/25/2019] [Accepted: 01/02/2020] [Indexed: 12/19/2022] Open
Abstract
Maternal obesity increases the risk of metabolic dysregulation in rodent offspring, especially when offspring are exposed to a high-fat (HF), obesogenic diet later in life. We previously demonstrated that maternal choline supplementation (MCS) in HF-fed mouse dams during gestation prevents fetal overgrowth and excess adiposity. In this study, we examined the long-term metabolic influence of MCS. C57BL/6J mice were fed a HF diet with or without choline supplementation prior to and during gestation. After weaning, their pups were exposed to either a HF or control diet for 6 weeks before measurements. Prenatal and post-weaning dietary treatments led to sexually dimorphic responses. In male offspring, while post-weaning HF led to impaired fasting glucose and worse glucose tolerance (p < 0.05), MCS in HF dams (HFCS) attenuated these changes. HFCS (versus maternal normal fat control) appeared to improve metabolic functioning of visceral adipose tissue during post-weaning HF feeding, preventing the elevation in leptin and increasing (p < 0.05) mRNA expression of insulin receptor substrate 1 (Irs1) that promotes peripheral insulin signaling in male offspring. In contrast, MCS had minimal effects on metabolic outcomes of female offspring. In conclusion, MCS during HF feeding in mice improves long-term blood glucose homeostasis in male offspring when they are faced with a postnatal obesogenic environment.
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A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells. PLoS One 2017; 12:e0170675. [PMID: 28249041 PMCID: PMC5331986 DOI: 10.1371/journal.pone.0170675] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Accepted: 01/09/2017] [Indexed: 11/19/2022] Open
Abstract
Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.
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Phosphoprotein Phosphatase 1 Is Required for Extracellular Calcium-Induced Keratinocyte Differentiation. BIOMED RESEARCH INTERNATIONAL 2016; 2016:3062765. [PMID: 27340655 PMCID: PMC4909930 DOI: 10.1155/2016/3062765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 04/05/2016] [Indexed: 11/17/2022]
Abstract
Extracellular calcium is a major regulator of keratinocyte differentiation in vitro and appears to play that role in vivo, but the mechanism is unclear. We have previously demonstrated that, following calcium stimulation, PIP5K1α is recruited by the E-cadherin-β-catenin complex to the plasma membrane where it provides the substrate PIP2 for both PI3K and PLC-γ1. This signaling pathway is critical for calcium-induced generation of second messengers including IP3 and intracellular calcium and keratinocyte differentiation. In this study, we explored the upstream regulatory mechanism by which calcium activates PIP5K1α and the role of this activation in calcium-induced keratinocyte differentiation. We found that treatment of human keratinocytes in culture with calcium resulted in an increase in serine dephosphorylation and PIP5K1α activation. PP1 knockdown blocked extracellular calcium-induced increase in serine dephosphorylation and activity of PIP5K1α and induction of keratinocyte differentiation markers. Knockdown of PLC-γ1, the downstream effector of PIP5K1α, blocked upstream dephosphorylation and PIP5K1α activation induced by calcium. Coimmunoprecipitation revealed calcium induced recruitment of PP1 to the E-cadherin-catenin-PIP5K1α complex in the plasma membrane. These results indicate that PP1 is recruited to the extracellular calcium-dependent E-cadherin-catenin-PIP5K1α complex in the plasma membrane to activate PIP5K1α, which is required for PLC-γ1 activation leading to keratinocyte differentiation.
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Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J Gastroenterol 2016; 22:2441-2459. [PMID: 26937133 PMCID: PMC4768191 DOI: 10.3748/wjg.v22.i8.2441] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 12/17/2015] [Accepted: 01/09/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.
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Wjidan K, Ibrahim E, Caszo B, Gnanou J, Singh H. Dysregulation of Glucose Homeostasis Following Chronic Exogenous Administration of Leptin in Healthy Sprague-Dawley Rats. J Clin Diagn Res 2015; 9:OF06-9. [PMID: 26816939 DOI: 10.7860/jcdr/2015/15594.7003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/14/2015] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Impaired glucose utilization is seen in chronic hyperleptinaemia associated conditions such as obesity and type 2 diabetes mellitus. It is unclear if this impaired glucose utilization is due to the effect of persistent hyperleptinaemia on insulin secretion from the beta cells of pancreas. AIM To examine the effects of chronic leptin administration on plasma glucose regulation in rats. MATERIALS AND METHODS Glucose challenge curves were plotted for male Sprague-Dawley rats treated with either normal saline (Control; n=8) or subcutaneous leptin injection for 42 days (60 μg/kg body weight/day; n=8). Plasma glucose and plasma insulin levels were measured at 0, 5, 10, 15, 20 and 25 minutes after glucose challenege. Skeletal muscle tissue was collected at the end of a glucose challenge for glucose transporter-4 protein content, insulin receptor and glucose transporter-4 mRNA expression. Data were analysed using repeated measures and one-way ANOVA with post-hoc analysis. RESULTS Chronic leptin treatment caused significantly higher fasting insulin level. Post glucose challenge, there was a significant increase in blood glucose levels and insulin level in the leptin treated rats. There was no significant difference in the skeletal muscle glucose transporter-4 content. However, leptin treated rats showed decreased mRNA expression of Insulin Receptor and glucose transporter-4 in the skeletal muscle. CONCLUSION Leptin administration for 42 days caused hyperinsulinaemia and decreased the expression of insulin receptors in insulin sensitive tissues leading to the development of an insulin resistance-like state in the rats.
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Affiliation(s)
- Khalil Wjidan
- Master's Student, Faculty of Medicine, Universiti Teknologi MARA , Sungai Buloh, Malaysia
| | - Effendi Ibrahim
- Lecturer, Faculty of Medicine, Universiti Teknologi MARA , Sungai Buloh, Malaysia
| | - Brinnell Caszo
- Associate Professor, Faculty of Medicine and Defence Health, National Defence University of Malaysia , Kem Sungai Besi, Kuala Lumpur, Malaysia
| | - Justin Gnanou
- Associate Professor, Faculty of Medicine and Defence Health, National Defence University of Malaysia , Kem Sungai Besi, Kuala Lumpur, Malaysia
| | - Harbindarjeet Singh
- Professor, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia; I-PerFFORM, Universiti Teknologi MARA , Selayang Campus, Selayang, Kuala Lumpur, Malaysia
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Abstract
The prevalence of diabetes is increasing rapidly worldwide. A cardinal feature of most forms of diabetes is the lack of insulin-producing capability, due to the loss of insulin-producing β-cells, impaired glucose-sensitive insulin secretion from the β-cell, or a combination thereof, the reasons for which largely remain elusive. Reversible phosphorylation is an important and versatile mechanism for regulating the biological activity of many intracellular proteins, which, in turn, controls a variety of cellular functions. For instance, significant changes in protein kinase activities and in protein phosphorylation patterns occur subsequent to the stimulation of insulin release by glucose. Therefore, the molecular mechanisms regulating the phosphorylation of proteins involved in the insulin secretory process by the β-cell have been extensively investigated. However, far less is known about the role and regulation of protein dephosphorylation by various protein phosphatases. Herein, we review extant data implicating serine/threonine and tyrosine phosphatases in various aspects of healthy and diabetic islet biology, ranging from control of hormonal stimulus-secretion coupling to mitogenesis and apoptosis.
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Affiliation(s)
- Henrik Ortsäter
- Biovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, SwedenBiovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, Sweden
| | - Nina Grankvist
- Biovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, Sweden
| | - Richard E Honkanen
- Biovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, Sweden
| | - Åke Sjöholm
- Biovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, SwedenBiovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, SwedenBiovation Park TelgeSödertälje, SwedenResearch UnitSödertälje Hospital, SE-152 86 Södertälje, SwedenDegenerative Disease ProgramSanford-Burnham Medical Research Institute, Del E. Webb Neuroscience, Aging and Stem Cell Research Center, 10901 North Torrey Pines Road, La Jolla, California 92037, USADepartment of Biochemistry and Molecular BiologyCollege of Medicine, University of South Alabama, Mobile, Alabama 36688, USADepartment of Internal MedicineSödertälje Hospital, Södertälje, Sweden
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Reither G, Chatterjee J, Beullens M, Bollen M, Schultz C, Köhn M. Chemical Activators of Protein Phosphatase-1 Induce Calcium Release inside Intact Cells. ACTA ACUST UNITED AC 2013; 20:1179-86. [DOI: 10.1016/j.chembiol.2013.07.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 07/08/2013] [Accepted: 07/12/2013] [Indexed: 01/15/2023]
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Li L, Sase A, Patil S, Sunyer B, Höger H, Smalla KH, Stork O, Lubec G. Distinct set of kinases induced after retrieval of spatial memory discriminate memory modulation processes in the mouse hippocampus. Hippocampus 2013; 23:672-83. [PMID: 23536525 DOI: 10.1002/hipo.22127] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2013] [Indexed: 12/15/2022]
Abstract
Protein phosphorylation and dephosphorylation events play a key role in memory formation and various protein kinases and phosphatases have been firmly associated with memory performance. Here, we determined expression changes of protein kinases and phosphatases following retrieval of spatial memory in CD1 mice in a Morris Water Maze task, using antibody microarrays and confirmatory Western blot. Comparing changes following single and consecutive retrieval, we identified stably and differentially expressed kinases, some of which have never been implicated before in memory functions. On the basis of these findings we define a small signaling network associated with spatial memory retrieval. Moreover, we describe differential regulation and correlation of expression levels with behavioral performance of polo-like kinase 1. Together with its recently observed genetic association to autism-spectrum disorders our data suggest a role of this kinase in balancing preservation and flexibility of learned behavior.
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Affiliation(s)
- Lin Li
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
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Targeting the untargetable: recent advances in the selective chemical modulation of protein phosphatase-1 activity. Curr Opin Chem Biol 2013; 17:361-8. [PMID: 23647984 DOI: 10.1016/j.cbpa.2013.04.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 04/04/2013] [Accepted: 04/09/2013] [Indexed: 01/03/2023]
Abstract
Protein phosphatase-1 (PP1) has long been neglected as a potential drug target owing to its misinterpreted unselective nature. However, growing evidence demonstrates that PP1 is highly selective in complex with regulatory proteins at the holoenzyme level, each of which is involved in different essential cellular signaling events. Here we summarize promising approaches to specifically activate or inhibit PP1 activity, and discuss remaining challenges and potential solutions. The summarized chemical tools pave the way for a better understanding of PP1's role in signaling networks, and the effects resulting from their application suggest their potential as future therapeutic candidates.
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Amitani M, Asakawa A, Amitani H, Inui A. The role of leptin in the control of insulin-glucose axis. Front Neurosci 2013; 7:51. [PMID: 23579596 PMCID: PMC3619125 DOI: 10.3389/fnins.2013.00051] [Citation(s) in RCA: 140] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Accepted: 03/18/2013] [Indexed: 12/21/2022] Open
Abstract
Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.
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Affiliation(s)
- Marie Amitani
- Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences Kagoshima, Japan
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Marroquí L, Gonzalez A, Ñeco P, Caballero-Garrido E, Vieira E, Ripoll C, Nadal A, Quesada I. Role of leptin in the pancreatic β-cell: effects and signaling pathways. J Mol Endocrinol 2012; 49:R9-17. [PMID: 22448029 DOI: 10.1530/jme-12-0025] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic β-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the β-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, β-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the β-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic β-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of β-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic β-cell.
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Affiliation(s)
- Laura Marroquí
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas-CIBERDEM, Elche, Spain
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2012; 19:233-47. [PMID: 22531108 DOI: 10.1097/med.0b013e3283542fb3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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