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Abdalla MMI. Advancing diabetes management: Exploring pancreatic beta-cell restoration's potential and challenges. World J Gastroenterol 2024; 30:4339-4353. [PMID: 39494103 PMCID: PMC11525866 DOI: 10.3748/wjg.v30.i40.4339] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Revised: 09/05/2024] [Accepted: 09/24/2024] [Indexed: 10/16/2024] Open
Abstract
Diabetes mellitus, characterized by chronic hyperglycemia due to insulin deficiency or resistance, poses a significant global health burden. Central to its pathogenesis is the dysfunction or loss of pancreatic beta cells, which are res-ponsible for insulin production. Recent advances in beta-cell regeneration research offer promising strategies for diabetes treatment, aiming to restore endogenous insulin production and achieve glycemic control. This review explores the physiological basis of beta-cell function, recent scientific advan-cements, and the challenges in translating these findings into clinical applications. It highlights key developments in stem cell therapy, gene editing technologies, and the identification of novel regenerative molecules. Despite the potential, the field faces hurdles such as ensuring the safety and long-term efficacy of regen-erative therapies, ethical concerns around stem cell use, and the complexity of beta-cell differentiation and integration. The review highlights the importance of interdisciplinary collaboration, increased funding, the need for patient-centered approaches and the integration of new treatments into comprehensive care strategies to overcome these challenges. Through continued research and collaboration, beta-cell regeneration holds the potential to revolutionize diabetes care, turning a chronic condition into a manageable or even curable disease.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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2
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Horváth D, Stráner P, Taricska N, Fazekas Z, Menyhárd DK, Perczel A. Influence of Trp-Cage on the Function and Stability of GLP-1R Agonist Exenatide Derivatives. J Med Chem 2024; 67:16757-16772. [PMID: 39254428 PMCID: PMC11440607 DOI: 10.1021/acs.jmedchem.4c01553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/22/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024]
Abstract
Exenatide (Ex4), a GLP-1 incretin mimetic polypeptide, is an effective therapeutic agent against diabetes and obesity. We highlight the indirect role of Ex4's structure-stabilizing Trp-cage (Tc) motif in governing GLP-1 receptor (GLP-1R) signal transduction. We use various Ex4 derivatives to explore how Tc compactness influences thermal stability, aggregation, enhancement of insulin secretion, and GLP-1R binding. We found that Ex4 variants decorated with fortified Tc motifs exhibit increased resistance to unfolding and aggregation but show an inverse relationship between the bioactivity and stability. Molecular dynamics simulations coupled with a rigid-body segmentation protocol to analyze dynamic interconnectedness revealed that the constrained Tc motifs remain intact within the receptor-ligand complexes but interfere with one of the major stabilizing contacts and recognition loci on the extracellular side of GLP-1R, dislodging the N-terminal activating region of the hormone mimetics, and restrict the free movement of TM6, the main signal transduction device of GLP-1R.
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Affiliation(s)
- Dániel Horváth
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Pál Stráner
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Nóra Taricska
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Zsolt Fazekas
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
- Hevesy
György PhD School of Chemistry, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - Dóra K. Menyhárd
- Medicinal
Chemistry Research Group, HUN-REN Research
Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117Budapest, Hungary
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
| | - András Perczel
- Medicinal
Chemistry Research Group, HUN-REN Research
Centre for Natural Sciences, Magyar Tudósok Körútja 2, H-1117Budapest, Hungary
- HUN-REN−ELTE
Protein Modeling Research Group, ELTE Eötvös
Loránd University, Pázmány Péter sétány 1/A, Budapest H-1117, Hungary
- Laboratory
of Structural Chemistry and Biology, ELTE
Eötvös Loránd University, Pázmány Péter sétány
1/A, Budapest H-1117, Hungary
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3
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Nomoto H. Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes. World J Diabetes 2023; 14:188-197. [PMID: 37035222 PMCID: PMC10075027 DOI: 10.4239/wjd.v14.i3.188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/13/2023] [Accepted: 02/09/2023] [Indexed: 03/15/2023] Open
Abstract
The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes (T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist (GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination (FRC) products, which comprise basal insulin and a GLP-1RA, have potent anti-hyperglycemic effects and reduce the undesirable side-effects of each component, such as body weight gain, hypoglycemia, and gastrointestinal symptoms. Two FRCs-insulin degludec/Liraglutide and insulin glargine/Lixisenatide-are now clinically available and, to date, several phase II/III trials have been conducted in particular groups of subjects with T2D. However, their utility in real-world clinical settings is of interest for most clinicians. Recently reported real-world clinical trials of these two FRCs in various situations have demonstrated their efficacy regarding glycemic control and the quality of life of people with T2D. Their long-term safety and efficacy require confirmation, but a treatment strategy that includes an FRC may be compatible with the concept of “well-balanced” therapy in certain groups of patients with T2D who have inadequate glycemic control.
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Affiliation(s)
- Hiroshi Nomoto
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Hokkaido, Japan
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Wang Y, Geng R, Zhao Y, Fang J, Li M, Kang SG, Huang K, Tong T. The gut odorant receptor and taste receptor make sense of dietary components: A focus on gut hormone secretion. Crit Rev Food Sci Nutr 2023; 64:6975-6989. [PMID: 36785901 DOI: 10.1080/10408398.2023.2177610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
Abstract
Odorant receptors (ORs) and taste receptors (TRs) are expressed primarily in the nose and tongue in which they transduce electrical signals to the brain. Advances in deciphering the dietary component-sensing mechanisms in the nose and tongue prompted research on the role of gut chemosensory cells. Acting as the pivotal interface between the body and dietary cues, gut cells "smell" and "taste" dietary components and metabolites by taking advantage of chemoreceptors-ORs and TRs, to maintain physiological homeostasis. Here, we reviewed this novel field, highlighting the latest discoveries pertinent to gut ORs and TRs responding to dietary components, their impacts on gut hormone secretion, and the mechanisms involved. Recent studies indicate that gut cells sense dietary components including fatty acid, carbohydrate, and phytochemical by activating relevant ORs, thereby modulating GLP-1, PYY, CCK, and 5-HT secretion. Similarly, gut sweet, umami, and bitter receptors can regulate the gut hormone secretion and maintain homeostasis in response to dietary components. A deeper understanding of the favorable influence of dietary components on gut hormone secretion via gut ORs and TRs, coupled with the facts that gut hormones are involved in diverse physiological or pathophysiological phenomena, may ultimately lead to a promising treatment for various human diseases.
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Affiliation(s)
- Yanan Wang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Ruixuan Geng
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Yuhan Zhao
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Jingjing Fang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Mengjie Li
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
| | - Seong-Gook Kang
- Department of Food Engineering, Mokpo National University, Muangun, Korea
| | - Kunlun Huang
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
| | - Tao Tong
- Key Laboratory of Precision Nutrition and Food Quality, Key Laboratory of Functional Dairy, Ministry of Education; College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, PR China
- Key Laboratory of Safety Assessment of Genetically Modified Organism (Food Safety), Ministry of Agriculture, Beijing, PR China
- Beijing Laboratory for Food Quality and Safety, Beijing, PR China
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5
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Odongo K, Hironao KY, Yamashita Y, Ashida H. Development of sandwich ELISAs for detecting glucagon-like peptide-1 secretion from intestinal L-cells and their application in STC-1 cells and mice. J Clin Biochem Nutr 2023; 72:28-38. [PMID: 36777078 PMCID: PMC9899920 DOI: 10.3164/jcbn.22-78] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/03/2022] [Indexed: 11/05/2022] Open
Abstract
Certain nutrients stimulate glucagon-like peptide-1 (GLP-1) secretion from the intestinal enteroendocrine L-cells, but due to rapid degradation by the DPP-4 enzyme, >90% is converted to inactive metabolite before reaching the target organs via circulation. Plants are a source of potent bioactive compounds that promote endogenous secretion of GLP-1 from L-cells. To search for the effective bioactive compound from a vast library of natural compounds, a reliable and low-cost assay is required considering the high cost of commercial assays. We developed a low-cost sandwich enzyme-linked immunosorbent assays (s-ELISAs) for detecting 'total', 'sensitive active', and 'wide-range active' GLP-1. The s-ELISAs exhibited high sensitivity with measurement ranges between 0.94~240, 0.98~62.5, and 4.8~4,480 pmol/L, respectively. High precision was observed; i.e., CVs within 5% and 20% for intra- and inter-assay variations, respectively, and excellent recovery of exogenous GLP-1 from assay buffer. The developed s-ELISAs had the same performance as the commercial kits and approximately 80% cheaper cost. For their application, cinnamtannin A2-induced GLP-1 secretion was confirmed in STC-1 cells consistent with our previous findings. The s-ELISAs were further validated by measuring plasma GLP-1 level in mice after oral administration of black soy bean seed coat extract containing cinnamtannin A2.
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Affiliation(s)
- Kevin Odongo
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Ken-yu Hironao
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan,To whom correspondence should be addressed. E-mail:
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Wang K, Cui X, Li F, Xia L, Wei T, Liu J, Fu W, Yang J, Hong T, Wei R. Glucagon receptor blockage inhibits β-cell dedifferentiation through FoxO1. Am J Physiol Endocrinol Metab 2023; 324:E97-E113. [PMID: 36383639 DOI: 10.1152/ajpendo.00101.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Glucagon-secreting pancreatic α-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells had remained elusive. In this study, we found that long-term glucagon intervention or glucagon intervention with the presence of palmitic acid downregulated β-cell-specific markers and inhibited insulin secretion in cultured β-cells. These results suggested that glucagon induced β-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced β-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated β-cell-specific markers and increased insulin content, suggesting that blockage of endogenous glucagon-GCGR signaling inhibited β-cell dedifferentiation. To investigate the possible mechanism, we found that glucagon decreased FoxO1 expression. FoxO1 inhibitor mimicked the effect of glucagon, whereas FoxO1 overexpression reversed the glucagon-induced β-cell dedifferentiation. In db/db mice and β-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased β-cell area, and inhibited β-cell dedifferentiation. In aged β-cell-specific FoxO1 knockout mice (with the blood glucose level elevated as a diabetic model), the glucose-lowering effect of GCGR mAb was attenuated and the plasma insulin level, β-cell area, and β-cell dedifferentiation were not affected by GCGR mAb. Our results proved that glucagon induced β-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel cross talk between α- and β-cells and is helpful to understand the pathophysiology of diabetes and discover new targets for diabetes treatment.NEW & NOTEWORTHY Glucagon-secreting pancreatic α-cells can interact with β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells has remained elusive. Our new finding shows that long-term glucagon induces β-cell dedifferentiation in cultured β-cells. FoxO1 inhibitor mimicks whereas glucagon signaling blockage by GCGR mAb reverses the effect of glucagon. In type 2 diabetic mice, GCGR mAb increases β-cell area, improves β-cell function, and inhibits β-cell dedifferentiation, and the effect is partially mediated by FoxO1.
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Affiliation(s)
- Kangli Wang
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Xiaona Cui
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Fei Li
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Li Xia
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Tianjiao Wei
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Junling Liu
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Wei Fu
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China
- Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
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Khamoshina MB, Artemenko YS, Bayramova AA, Ryabova VA, Orazov MR. Polycystic ovary syndrome and obesity: a modern paradigm. RUDN JOURNAL OF MEDICINE 2022. [DOI: 10.22363/2313-0245-2022-26-4-382-395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Polycystic ovary syndrome is a heterogeneous endocrine disease that affects women of childbearing age. The pathogenesis of polycystic ovary syndrome has not been fully studied to date, its paradigm considers the genetic determinism of the manifestation of hormonal and metabolic disorders, which are considered to be criteria for the verification of the disease (hyperandrogenism, oligo/anovulation and/or polycystic ovarian transformation during ultrasound examination (ultrasound). This review discusses the main ways of interaction between hyperandrogenism, insulin resistance and obesity and their role in the pathogenesis of polycystic ovary syndrome, as well as possible methods of treatment for this category of patients. The review analyzes the role of hyperandrogenism and insulin resistance in the implementation of the genetic scenario of polycystic ovary syndrome and finds out the reasons why women with polycystic ovary syndrome often demonstrate the presence of a «metabolic trio» - hyperinsulinemia, insulin resistance and type 2 diabetes mellitus. It is noted that obesity is not included in the criteria for the diagnosis of polycystic ovary syndrome, but epidemiological data confirm the existence of a relationship between these diseases. Obesity, especially visceral, which is often found in women with polycystic ovary syndrome, enhances and worsens metabolic and reproductive outcomes with polycystic ovary syndrome, as well as increases insulin resistance and compensatory hyperinsulinemia, which, in turn, stimulates adipogenesis and suppresses lipolysis. Obesity increases the sensitivity of tech cells to luteinizing hormone stimulation and enhances functional hyperandrogenism of the ovaries, increasing the production of androgens by the ovaries. Excess body weight is associated with a large number of inflammatory adipokines, which, in turn, contribute to the growth of insulin resistance and adipogenesis. Obesity and insulin resistance exacerbate the symptoms of hyperandrogenism, forming a vicious circle that contributes to the development of polycystic ovary syndrome. These data allow us to conclude that bariatric surgery can become an alternative to drugs (metformin, thiazolidinedione analogs of glucagon-like peptide-1), which has shown positive results in the treatment of patients with polycystic ovary syndrome and obesity.
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Liaw CC, Huang HT, Liu HK, Lin YC, Zhang LJ, Wei WC, Shen CC, Wu CL, Huang CY, Kuo YH. Cucurbitane-type triterpenoids from the vines of Momordica charantia and their anti-inflammatory, cytotoxic, and antidiabetic activity. PHYTOCHEMISTRY 2022; 195:113026. [PMID: 34890886 DOI: 10.1016/j.phytochem.2021.113026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/18/2021] [Accepted: 11/20/2021] [Indexed: 06/13/2023]
Abstract
Phytochemical investigation of the ethanol extract from wild Momordica charantia vines has resulted in isolation of seven cucurbitane-type triterpenoids, including six undescribed compounds, kuguaovins H‒M, and the known compound, momordicoside K. The structures of the isolated compounds were elucidated on the basis of spectroscopic analyses, including 1D and 2D NMR, and MS experiments. The chemical structure of momordicoside K was determined for the first time by X-ray crystallographic analysis and its absolute configuration assigned. The cytotoxicity against four human tumor cell lines and anti-inflammatory activities on LPS-stimulated RAW264.7 macrophages were evaluated. Of the isolates, kaguaovin L exhibited potential cytotoxicity against MCF-7, HEp-2, Hep-G2, and WiDr cancer cell lines and showed moderate anti-NO production activity. In addition, kuguaovins H and J also showed the stimulatory effect of GLP-1 secretion on the murine intestinal secretin tumor cell line (STC-1).
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Affiliation(s)
- Chia-Ching Liaw
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan; Department of Biochemical Science and Technology, National Chiayi University, Chiayi, 60004, Taiwan
| | - Hung-Tse Huang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan; Department of Biochemical Science & Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Hui-Kang Liu
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan
| | - Yu-Chi Lin
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan; Department of Marine Biotechnology and Resources, National Sun Ya-sen University, Kaohsiung, 80424, Taiwan
| | - Li-Jie Zhang
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan
| | - Wen-Chi Wei
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan
| | - Chien-Chang Shen
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan
| | - Chia-Lun Wu
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan; Department of Food Science, National Ilan University, Ilan, 26047, Taiwan
| | - Chung-Yi Huang
- Department of Food Science, National Ilan University, Ilan, 26047, Taiwan.
| | - Yao-Haur Kuo
- National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, 11201, Taiwan; Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
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Gu L, Wang D, Cui X, Wei T, Yang K, Yang J, Wei R, Hong T. Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic β-Cell Regeneration In Situ in Type 1 Diabetic Mice. J Diabetes Res 2021; 2021:7765623. [PMID: 39280767 PMCID: PMC11401728 DOI: 10.1155/2021/7765623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/01/2021] [Accepted: 10/23/2021] [Indexed: 09/18/2024] Open
Abstract
Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote the recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β-cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β-cells/α-cells. Our study evaluated the effects of liraglutide, GCGR mAb monotherapy, and combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.
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Affiliation(s)
- Liangbiao Gu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Dandan Wang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Xiaona Cui
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Tianjiao Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Kun Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
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10
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Xing C, Lv B, Zhao H, Wang D, Li X, He B. Metformin and exenatide upregulate hepatocyte nuclear factor-4α, sex hormone binding globulin levels and improve hepatic triglyceride deposition in polycystic ovary syndrome with insulin resistance rats. J Steroid Biochem Mol Biol 2021; 214:105992. [PMID: 34478829 DOI: 10.1016/j.jsbmb.2021.105992] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/18/2021] [Accepted: 08/29/2021] [Indexed: 12/25/2022]
Abstract
OBJECTIVE To explore the efficacy and underlying mechanisms of metformin and exenatide in reversing reproductive and metabolic disturbances in letrozole combined with high-fat diet-induced polycystic ovary syndrome (PCOS) rats. METHODS Rats with PCOS and insulin resistance (IR) were induced by intra-gastric instillation of letrozole combined with a high-fat diet and verified by histological screening of vaginal exfoliated cells. After metformin and exenatide supplementation, body weight, chow intake and ovarian morphology were observed. Serum biochemical profiles were analyzed using ELISA, while the levels of key anabolism-related proteins, including sex hormone binding globulin (SHBG), hepatocyte nuclear factor-4α (HNF-4α), PI3K, and AKT, were determined using western blotting. RESULTS The estrus cycle and ovarian morphology of rats with PCOS and IR were significantly recovered following metformin and exenatide treatment, with decreased body weight and chow intake. Furthermore, PCOS-induced changes in metabolic disorders including IR and hepatic triglyceride (TG) deposition, and hyperandrogenemia were reversed by treatment with both drugs. Specifically, the levels of HNF-4α and SHBG in liver tissue of rats with PCOS and IR were upregulated significantly. CONCLUSIONS Both metformin and exenatide could recover the estrous cycle and ovarian morphology, reduce body weight and high-fat chow intake, and improve glycolipid metabolism disorders and hyperandrogenemia in PCOS with IR rat models. Interestingly, our findings also highlight the potential of both therapeutic agents for improving IR by regulating the liver PI3K/AKT pathway, reducing the deposition of hepatic TG, as well as upregulating the levels of SHBG and HNF-4α in PCOS with IR rat liver tissue.
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Affiliation(s)
- Chuan Xing
- Department of Endocrinology, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Bo Lv
- Department of Endocrinology, Dalian Third People's Hospital, 116000, Dalian, China
| | - Han Zhao
- Department of Endocrinology, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Dongxu Wang
- Department of General Internal Medicine, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Xuesong Li
- Department of Endocrinology, Shengjing Hospital of China Medical University, 110004, Shenyang, China
| | - Bing He
- Department of Endocrinology, Shengjing Hospital of China Medical University, 110004, Shenyang, China.
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11
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Zheng W, Li L, Li H. Phytochemicals modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Biochem Pharmacol 2021; 197:114817. [PMID: 34717897 DOI: 10.1016/j.bcp.2021.114817] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/22/2021] [Accepted: 10/25/2021] [Indexed: 11/19/2022]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor-based therapies have been developed and extensively applied in clinical practice. GLP-1 plays an important role in improving glycemic homeostasis by stimulating insulin biosynthesis and secretion, suppressing glucagon activity, delaying gastric emptying, and reducing appetite and food ingestion. Furthermore, GLP-1 has positive effects on β-cell function by promoting β-cell proliferation and neogenesis while simultaneously reducing apoptosis. Here, we summarize possible mechanisms of action of GLP-1 upon pancreatic islets as well as describe phytochemicals that modulate pancreatic islet β cell function through glucagon-like peptide-1-related mechanisms. Together, this information provides potential lead compound candidates against diabetes that function as GLP-1 receptor-based pharmacotherapy.
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Affiliation(s)
- Wanfang Zheng
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China
| | - Linghuan Li
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China
| | - Hanbing Li
- Institute of Pharmacology, Zhejiang University of Technology, Hangzhou 310014, People's Republic of China; Section of Endocrinology, School of Medicine, Yale University, New Haven 06520, USA.
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12
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Lee LC, Hou YC, Hsieh YY, Chen YH, Shen YC, Lee IJ, Monica Shih MC, Hou WC, Liu HK. Dietary supplementation of rutin and rutin-rich buckwheat elevates endogenous glucagon-like peptide 1 levels to facilitate glycemic control in type 2 diabetic mice. J Funct Foods 2021; 85:104653. [DOI: 10.1016/j.jff.2021.104653] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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13
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Yao M, Zhang J, Li Z, Bai X, Ma J, Li Y. Liraglutide Protects Nucleus Pulposus Cells Against High-Glucose Induced Apoptosis by Activating PI3K/Akt/ mTOR/Caspase-3 and PI3K/Akt/GSK3β/Caspase-3 Signaling Pathways. Front Med (Lausanne) 2021; 8:630962. [PMID: 33681258 PMCID: PMC7933515 DOI: 10.3389/fmed.2021.630962] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Background and Objective: Diabetes mellitus (DM) is reportedly a significant risk factor for intervertebral disc degeneration (IDD). Incretin system and particularly glucagon-like peptide 1 (GLP-1) because of its glucose-lowering effects has become an important target in therapeutic strategies of type 2 diabetes (T2D). Liraglutide is a GLP-1 receptor (GLP-1R) agonist with glucoregulatory and insulinotropic functions as well as regulatory functions on cell proliferation, differentiation, and apoptosis. However, little is known on the roles and signaling pathways of apoptosis protecting effects of liraglutide in IDD. This study aimed to investigate the potential protective effects of liraglutide against high glucose-induced apoptosis of nucleus pulposus cells (NPCs) and the possible involved signaling pathways. Methods: The human NPCs were incubated with 100 nM liraglutide alone or in combination with LY294002 (PI3K inhibitor), rapamycin (mTOR inhibitor), and SB216763 (GSK3β inhibitor) in a high glucose culture for 48 h. The four groups were assessed further for apoptosis and genes expressions. The apoptotic effect was evaluated by flow cytometry and further confirmed by cell death detection enzyme-linked immunoassay plus (ELISAPLUS). The gene and protein expression levels were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting techniques. The results were comparatively assessed between the four groups. Results: The results confirmed the presence of GLP-1R in the NPCs indicating that liraglutide inhibited the high glucose-induced apoptosis, which was blocked by silencing GLP-1R with siRNA. Moreover, liraglutide stimulated the phosphorylation of Akt, mTOR and GSK3β. Treatment with LY294002 significantly increased the apoptosis of NPCs and reduced the levels of their downstream substrates (p-AKT, p-mTOR, and p-GSK3β). Further assessments revealed that activation of mTOR and GSK3β was almost completely inhibited by rapamycin and SB216763, respectively, which significantly increased the caspase-3 levels. Conclusion: Liraglutide could protect NPCs against high glucose-induced apoptosis by activating the PI3K/AKT/mTOR/caspase-3 and PI3K/AKT/GSK3β/caspase-3 signaling pathways.
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Affiliation(s)
- Mingyan Yao
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China.,Department of Endocrinology, Baoding No.1 Central Hospital, Baoding, China
| | - Jing Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Baoding, China
| | - Zhihong Li
- Department of Endocrinology, Baoding No.1 Central Hospital, Baoding, China
| | - Xiaoliang Bai
- Department of Orthopedics, Baoding No.1 Central Hospital, Baoding, China
| | - Jinhui Ma
- Department of Endocrinology, Affiliated Hospital of Hebei University, Baoding, China
| | - Yukun Li
- Department of Endocrinology, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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14
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Wang KL, Tao M, Wei TJ, Wei R. Pancreatic β cell regeneration induced by clinical and preclinical agents. World J Stem Cells 2021; 13:64-77. [PMID: 33584980 PMCID: PMC7859987 DOI: 10.4252/wjsc.v13.i1.64] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 11/16/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetes, one of the most common chronic diseases in the modern world, has pancreatic β cell deficiency as a major part of its pathophysiological mechanism. Pancreatic regeneration is a potential therapeutic strategy for the recovery of β cell loss. However, endocrine islets have limited regenerative capacity, especially in adult humans. Almost all hypoglycemic drugs can protect β cells by inhibiting β cell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress. Several agents, including glucagon-like peptide-1 and γ-aminobutyric acid, have been shown to promote β cell proliferation, which is considered the main source of the regenerated β cells in adult rodents, but with less clarity in humans. Pancreatic progenitor cells might exist and be activated under particular circumstances. Artemisinins and γ-aminobutyric acid can induce α-to-β cell conversion, although some disputes exist. Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion, and pharmacological research into FoxO1 inhibition is ongoing. Other cells, including pancreatic acinar cells, can transdifferentiate into β cells, and clinical and preclinical strategies are currently underway. In this review, we summarize the clinical and preclinical agents used in different approaches for β cell regeneration and make some suggestions regarding future perspectives for clinical application.
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Affiliation(s)
- Kang-Li Wang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Ming Tao
- Department of General Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Tian-Jiao Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
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15
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Li X, Yang X, Umar M, Zhang Z, Luo W, Fan Y, Ma D, Li M. Expression of a novel dual-functional polypeptide and its pharmacological action research. Life Sci 2020; 267:118890. [PMID: 33359743 DOI: 10.1016/j.lfs.2020.118890] [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: 08/29/2020] [Revised: 11/30/2020] [Accepted: 12/08/2020] [Indexed: 11/15/2022]
Abstract
AIMS To develop a dual-functional medicine for hypoglycemic and anti-thrombus. MAIN METHODS The long-acting glucagon like peptide-1 (5×GLP-1) and nattokinase (NK) were cloned by SOE PCR and gained the GLP-1 and NK fusion polypeptide after transformed into E. coli. Use of mice models for the hypoglycemic and anti-thrombus activity of the fusion polypeptide. Balb/C mice were given the carrageenan by intraperitoneal injection to induce tail thrombus models. Type 2 diabetes mellitus mice model was used to research the hypoglycemic function of the fusion polypeptide. KEY FINDINGS Results showed that the fusion polypeptide could significantly prevent thrombus formation after oral administration. Continuous administration for 15 days, fasting blood glucose levels of the experimental group decreased to nearly normal levels. SIGNIFICANCE The present study investigated the expression, purification and functional activity of the rolGLP-1 and NK fusion polypeptide, which provided a foundation for further studying the detailed pharmaceutical mechanism and drug development.
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Affiliation(s)
- Xiaodan Li
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China; School of Mental Health, Jining Medical University, Jining, Shandong 272067, China
| | - Xingkai Yang
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Muhammad Umar
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Zhixuan Zhang
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Wenya Luo
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Yu Fan
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Daocheng Ma
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China
| | - Minggang Li
- State Key Laboratory of Medical Chemical Biology, Key Laboratory for Bioactive Materials of the Ministry of Education, College of Life Science, Nankai University, 300071 Tianjin, China.
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16
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Dragano NRV, Fernø J, Diéguez C, López M, Milbank E. Reprint of: Recent Updates on Obesity Treatments: Available Drugs and Future Directions. Neuroscience 2020; 447:191-215. [PMID: 33046217 DOI: 10.1016/j.neuroscience.2020.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.
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Affiliation(s)
- Nathalia R V Dragano
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway
| | - Carlos Diéguez
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Miguel López
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Edward Milbank
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
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17
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Marrano N, Biondi G, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. Functional loss of pancreatic islets in type 2 diabetes: How can we halt it? Metabolism 2020; 110:154304. [PMID: 32599081 DOI: 10.1016/j.metabol.2020.154304] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/14/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as "symptomatic" medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed.
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Affiliation(s)
- Nicola Marrano
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Giuseppina Biondi
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Angelo Cignarelli
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Sebastio Perrini
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Luigi Laviola
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Annalisa Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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18
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Dragano NRV, Fernø J, Diéguez C, López M, Milbank E. Recent Updates on Obesity Treatments: Available Drugs and Future Directions. Neuroscience 2020; 437:215-239. [PMID: 32360593 DOI: 10.1016/j.neuroscience.2020.04.034] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 04/17/2020] [Accepted: 04/20/2020] [Indexed: 12/12/2022]
Abstract
In the last thirty years, obesity has reached epidemic proportions and is now regarded as a major health issue in contemporary society trending to serious economic and social burdens. The latest projections of the World Health Organization are alarming. By 2030, nearly 60% of the worldwide population could be either obese or overweight, highlighting the needs to find innovative treatments. Currently, bariatric surgery is the most effective way to efficiently lower body mass. Although great improvements in terms of recovery and patient care were made in these surgical procedures, bariatric surgery remains an option for extreme forms of obesity and seems unable to tackle obesity pandemic expansion. Throughout the last century, numerous pharmacological strategies targeting either peripheral or central components of the energy balance regulatory system were designed to reduce body mass, some of them reaching sufficient levels of efficiency and safety. Nevertheless, obesity drug therapy remains quite limited on its effectiveness to actually overcome the obesogenic environment. Thus, innovative unimolecular polypharmacology strategies, able to simultaneously target multiple actors involved in the obesity initiation and expansion, were developed during the last ten years opening a new promising avenue in the pharmacological management of obesity. In this review, we first describe the clinical features of obesity-associated conditions and then focus on the outcomes of currently approved drug therapies for obesity as well as new ones expecting to reach the clinic in the near future.
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Affiliation(s)
- Nathalia R V Dragano
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
| | - Johan Fernø
- Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway
| | - Carlos Diéguez
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Miguel López
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain
| | - Edward Milbank
- NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), 15706, Spain.
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19
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Ferdaoussi M, Smith N, Lin H, Bautista A, Spigelman AF, Lyon J, Dai X, Manning Fox JE, MacDonald PE. Improved glucose tolerance with DPPIV inhibition requires β-cell SENP1 amplification of glucose-stimulated insulin secretion. Physiol Rep 2020; 8:e14420. [PMID: 32339440 PMCID: PMC7185381 DOI: 10.14814/phy2.14420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 03/19/2020] [Accepted: 03/20/2020] [Indexed: 01/09/2023] Open
Abstract
Pancreatic islet insulin secretion is amplified by both metabolic and receptor-mediated signaling pathways. The incretin-mimetic and DPPIV inhibitor anti-diabetic drugs increase insulin secretion, but in humans this can be variable both in vitro and in vivo. We examined the correlation of GLP-1 induced insulin secretion from human islets with key donor characteristics, glucose-responsiveness, and the ability of glucose to augment exocytosis in β-cells. No clear correlation was observed between several donor or organ processing parameters and the ability of Exendin 4 to enhance insulin secretion. The ability of glucose to facilitate β-cell exocytosis was, however, significantly correlated with responses to Exendin 4. We therefore studied the effect of impaired glucose-dependent amplification of insulin exocytosis on responses to DPPIV inhibition (MK-0626) in vivo using pancreas and β-cell specific sentrin-specific protease-1 (SENP1) mice which exhibit impaired metabolic amplification of insulin exocytosis. Glucose tolerance was improved, and plasma insulin was increased, following either acute or 4 week treatment of wild-type (βSENP1+/+ ) mice with MK-0626. This DPPIV inhibitor was ineffective in βSENP1+/- or βSENP1- / - mice. Finally, we confirm impaired exocytotic responses of β-cells and reduced insulin secretion from islets of βSENP1- / - mice and show that the ability of Exendin 4 to enhance exocytosis is lost in these cells. Thus, an impaired ability of glucose to amplify insulin exocytosis results in a deficient effect of DPPIV inhibition to improve in vivo insulin responses and glucose tolerance.
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Affiliation(s)
- Mourad Ferdaoussi
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Nancy Smith
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Haopeng Lin
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Austin Bautista
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Aliya F. Spigelman
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - James Lyon
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - XiaoQing Dai
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Jocelyn E. Manning Fox
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
| | - Patrick E. MacDonald
- Department of Pharmacology and Alberta Diabetes InstituteUniversity of AlbertaEdmontonABCanada
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20
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Brial F, Alzaid F, Sonomura K, Kamatani Y, Meneyrol K, Le Lay A, Péan N, Hedjazi L, Sato TA, Venteclef N, Magnan C, Lathrop M, Dumas ME, Matsuda F, Zalloua P, Gauguier D. The Natural Metabolite 4-Cresol Improves Glucose Homeostasis and Enhances β-Cell Function. Cell Rep 2020; 30:2306-2320.e5. [PMID: 32075738 DOI: 10.1016/j.celrep.2020.01.066] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 10/26/2019] [Accepted: 01/22/2020] [Indexed: 02/09/2023] Open
Abstract
Exposure to natural metabolites contributes to the risk of cardiometabolic diseases (CMDs). Through metabolome profiling, we identify the inverse correlation between serum concentrations of 4-cresol and type 2 diabetes. The chronic administration of non-toxic doses of 4-cresol in complementary preclinical models of CMD reduces adiposity, glucose intolerance, and liver triglycerides, enhances insulin secretion in vivo, stimulates islet density and size, and pancreatic β-cell proliferation, and increases vascularization, suggesting activated islet enlargement. In vivo insulin sensitivity is not affected by 4-cresol. The incubation of mouse isolated islets with 4-cresol results in enhanced insulin secretion, insulin content, and β-cell proliferation of a magnitude similar to that induced by GLP-1. In both CMD models and isolated islets, 4-cresol is associated with the downregulated expression of the kinase DYRK1A, which may mediate its biological effects. Our findings identify 4-cresol as an effective regulator of β-cell function, which opens up perspectives for therapeutic applications in syndromes of insulin deficiency.
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Affiliation(s)
- Francois Brial
- Université de Paris, INSERM UMR 1124, 75006 Paris, France
| | - Fawaz Alzaid
- Sorbonne Université, Université Paris Descartes, INSERM UMR_S 1138, Cordeliers Research Centre, 75006 Paris, France
| | - Kazuhiro Sonomura
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Life Science Research Center, Technology Research Laboratory, Shimadzu, Kyoto 604-8511, Japan
| | - Yoichiro Kamatani
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Kelly Meneyrol
- Université de Paris, Unit of Functional and Adaptive Biology, UMR 8251, CNRS, 4 rue Marie Andrée Lagroua Weill-Halle, 75013 Paris, France
| | - Aurélie Le Lay
- Université de Paris, INSERM UMR 1124, 75006 Paris, France
| | - Noémie Péan
- Université de Paris, INSERM UMR 1124, 75006 Paris, France
| | | | - Taka-Aki Sato
- Life Science Research Center, Technology Research Laboratory, Shimadzu, Kyoto 604-8511, Japan
| | - Nicolas Venteclef
- Sorbonne Université, Université Paris Descartes, INSERM UMR_S 1138, Cordeliers Research Centre, 75006 Paris, France
| | - Christophe Magnan
- Université de Paris, Unit of Functional and Adaptive Biology, UMR 8251, CNRS, 4 rue Marie Andrée Lagroua Weill-Halle, 75013 Paris, France
| | - Mark Lathrop
- McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada
| | - Marc-Emmanuel Dumas
- Imperial College London, Section of Biomolecular Medicine, Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, UK
| | - Fumihiko Matsuda
- Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
| | - Pierre Zalloua
- Lebanese American University, School of Medicine, Beirut 1102 2801, Lebanon.
| | - Dominique Gauguier
- Université de Paris, INSERM UMR 1124, 75006 Paris, France; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC H3A 0G1, Canada.
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21
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Metabolic dysfunction in polycystic ovary syndrome: Pathogenic role of androgen excess and potential therapeutic strategies. Mol Metab 2020; 35:100937. [PMID: 32244180 PMCID: PMC7115104 DOI: 10.1016/j.molmet.2020.01.001] [Citation(s) in RCA: 245] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/16/2022] Open
Abstract
Background Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited. Scope of review This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions. Major conclusions Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
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Zhu L, Zhou J, Pan Y, Lv J, Liu Y, Yu S, Zhang Y. Glucagon-like peptide-1 receptor expression and its functions are regulated by androgen. Biomed Pharmacother 2019; 120:109555. [DOI: 10.1016/j.biopha.2019.109555] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/11/2019] [Accepted: 10/11/2019] [Indexed: 11/27/2022] Open
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Mohammed A, Ibrahim MA, Tajuddeen N, Aliyu AB, Isah MB. Antidiabetic potential of anthraquinones: A review. Phytother Res 2019; 34:486-504. [PMID: 31773816 DOI: 10.1002/ptr.6544] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 10/03/2019] [Accepted: 10/19/2019] [Indexed: 01/03/2023]
Affiliation(s)
- Aminu Mohammed
- Department of BiochemistryAhmadu Bello University Zaria Nigeria
| | | | - Nasir Tajuddeen
- Department of ChemistryAhmadu Bello University Zaria Nigeria
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Jun Y, Lee J, Choi S, Yang JH, Sander M, Chung S, Lee SH. In vivo-mimicking microfluidic perfusion culture of pancreatic islet spheroids. SCIENCE ADVANCES 2019; 5:eaax4520. [PMID: 31807701 PMCID: PMC6881167 DOI: 10.1126/sciadv.aax4520] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 09/25/2019] [Indexed: 05/18/2023]
Abstract
Native pancreatic islets interact with neighboring cells by establishing three-dimensional (3D) structures, and are surrounded by perfusion at an interstitial flow level. However, flow effects are generally ignored in islet culture models, although cell perfusion is known to improve the cell microenvironment and to mimic in vivo physiology better than static culture systems. Here, we have developed functional islet spheroids using a microfluidic chip that mimics interstitial flow conditions with reduced shear cell damage. Dynamic culture, compared to static culture, enhanced islet health and maintenance of islet endothelial cells, reconstituting the main component of islet extracellular matrix within spheroids. Optimized flow condition allowed localization of secreted soluble factors near spheroids, facilitating diffusion-mediated paracrine interactions within islets, and enabled long-term maintenance of islet morphology and function for a month. The proposed model can aid islet preconditioning before transplantation and has potential applications as an in vitro model for diabetic drug testing.
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Affiliation(s)
- Yesl Jun
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
| | - JaeSeo Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Seongkyun Choi
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
| | - Ji Hun Yang
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
- Next & Bio Inc., Seoul National University, Seoul 08826, Republic of Korea
| | - Maike Sander
- Departments of Pediatrics and Cellular and Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA
| | - Seok Chung
- School of Mechanical Engineering, Korea University, Seoul 02841, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
| | - Sang-Hoon Lee
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
- School of Biomedical Engineering, Korea University, Seoul 02841, Republic of Korea
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Lin LC, Lee LC, Huang C, Chen CT, Song JS, Shiao YJ, Liu HK. Effects of boschnaloside from Boschniakia rossica on dysglycemia and islet dysfunction in severely diabetic mice through modulating the action of glucagon-like peptide-1. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 62:152946. [PMID: 31102890 DOI: 10.1016/j.phymed.2019.152946] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 05/01/2019] [Accepted: 05/04/2019] [Indexed: 06/09/2023]
Abstract
BACKGROUND Boschniakia rossica is a well-known traditional Chinese medicine for tonifying kidney and improving impotence. Boschnaloside is the major iridoid glycoside in this herb but therapeutic benefits for diabetes remained to be evaluated. HYPOTHESIS/PURPOSE The current investigation aims to study the antidiabetic effect and the underlying pharmacological mechanisms. STUDY DESIGN AND METHODS Receptor binding, cAMP production, Ins secretion, glucagon-like peptide 1 (GLP-1) secretion, and dipeptidyl peptidase-4 activity assays were performed. Therapeutic benefits of orally administrated boschnaloside (150 and 300 mg/kg/day) were evaluated using severely 12-week old female diabetic db/db mice (Hemoglobin A1c >10%). RESULTS Oral treatment of boschnaloside for 4 weeks improved diabetic symptoms including fasting blood sugar, hemoglobin A1c, glucose intolerance, and Homeostatic Model Assessment of Ins Resistance, accompanied by circulating GLP-1active and adiponectin levels. In addition, bochnaloside treatment improved islet/β cell function associated with an alteration of the pancreatic and duodenal homeobox 1 level. It was shown that boschnaloside interacted with the extracellular domain of GLP-1 receptor and enhanced glucose stimulated Ins secretion. Boschnaloside also augmented the insulinotropic effect of GLP-1. Finally, the presence of boschnaloside caused a reduction of dipeptidyl peptidase-4 activity while enhanced GLP-1 secretion from STC-1 cells. CONCLUSION It appears that bochnaloside at oral dosage greater than 150 mg/kg/day exerts antidiabetic effects in vivo through modulating the action of GLP-1.
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Affiliation(s)
- Lie-Chwen Lin
- Division of Chinese Medicine Literature and Informatics, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Lin-Chien Lee
- Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine, National YangMing University, Taipei, Taiwan, ROC; Department of Earth and Life Sciences, University of Taipei, Taipei, Taiwan, ROC
| | - Chiung-Tong Chen
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC
| | - Jen-Shin Song
- Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli, Taiwan, ROC
| | - Young-Ji Shiao
- Division of Basic Chinese Medicine,National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC; Institute of Biopharmaceutical Science, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Hui-Kang Liu
- Division of Basic Chinese Medicine,National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC; Ph.D Program for the Clinical Drug Discovery from Herbal Medicine, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, ROC.
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Alavi SE, Cabot PJ, Moyle PM. Glucagon-Like Peptide-1 Receptor Agonists and Strategies To Improve Their Efficiency. Mol Pharm 2019; 16:2278-2295. [PMID: 31050435 DOI: 10.1021/acs.molpharmaceut.9b00308] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is increasing in global prevalence and is associated with serious health problems (e.g., cardiovascular disease). Various treatment options are available for T2DM, including the incretin hormone glucagon-like peptide-1 (GLP-1). GLP-1 is a therapeutic peptide secreted from the intestines following food intake, which stimulates the secretion of insulin from the pancreas. The native GLP-1 has a very short plasma half-life, owning to renal clearance and degradation by the enzyme dipeptidyl peptidase-4. To overcome this issue, various GLP-1 agonists with increased resistance to proteolytic degradation and reduced renal clearance have been developed, with several currently marketed. Strategies, such as controlled release delivery systems, methods to reduce renal clearance (e.g., PEGylation and conjugation to antibodies), and methods to improve proteolytic stability (e.g., stapling, cyclization, and glycosylation) provide means to further improve the ability of GLP-1 analogs. These will be discussed in this literature review.
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Affiliation(s)
- Seyed Ebrahim Alavi
- School of Pharmacy , The University of Queensland , Woolloongabba , 4102 , Australia
| | - Peter J Cabot
- School of Pharmacy , The University of Queensland , Woolloongabba , 4102 , Australia
| | - Peter M Moyle
- School of Pharmacy , The University of Queensland , Woolloongabba , 4102 , Australia
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Wang Y, Li M, Ni Z. Primary study on the hypoglycemic mechanism of 5rolGLP-HV in STZ-induced type 2 diabetes mellitus mice. J Biosci 2018. [DOI: 10.1007/s12038-018-9809-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Abstract
AMP-activated protein kinase (AMPK) is the main cellular energy sensor. Activated following a depletion of cellular energy stores, AMPK will restore the energy homoeostasis by increasing energy production and limiting energy waste. At a central level, the AMPK pathway will integrate peripheral signals (mostly hormones and metabolites) through neuronal networks. Hypothalamic AMPK is directly implicated in feeding behaviour, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). It also participates in other metabolic functions: glucose and muscle metabolisms, as well as hepatic function. Numerous anti-obesity and/or antidiabetic agents, such as nicotine, metformin and liraglutide, are known to induce their effects through a modulation of AMPK pathway, either at central or at peripheral levels. Moreover, the weight-gaining side effects of antipsychotic drugs, such as olanzapine, are also mediated by hypothalamic AMPK. Therefore, considering hypothalamic AMPK as a therapeutic target in metabolic diseases appears as an interesting strategy due to its implication in feeding and energy expenditure, the two sides of the energy balance equation.
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Affiliation(s)
- Miguel López
- NeurObesity Group, Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
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Abstract
OBJECTIVES Modulation of cholecystokinin (CCK) receptors has been shown to influence pancreatic endocrine function. METHODS We assessed the impact of the CCKA and CCKB receptor modulators, (pGlu-Gln)-CCK-8 and gastrin-17, respectively, on β-cell secretory function, proliferation and apoptosis and glucose tolerance, and investigating alterations of CCK and gastrin islet expression in diabetes. RESULTS Initially, the presence of CCK and gastrin, and expression of their receptors were evidenced in β-cell lines and mouse islets. (pGlu-Gln)-CCK-8 and gastrin-17 stimulated insulin secretion from BRIN-BD11 and 1.1B4 β-cells, associated with no effect on membrane potential or [Ca]i. Only (pGlu-Gln)-CCK-8 possessed insulin secretory actions in isolated islets. In agreement, (pGlu-Gln)-CCK-8 improved glucose disposal and glucose-induced insulin release in mice. In addition, (pGlu-Gln)-CCK-8 evoked clear satiety effects. Interestingly, islet colocalization of CCK with glucagon was elevated in streptozotocin- and hydrocortisone-induced diabetic mice, whereas gastrin coexpression in α cells was reduced. In contrast, gastrin colocalization within β-cells was higher in diabetic mice, while CCK coexpression with insulin was decreased in insulin-deficient mice. (pGlu-Gln)-CCK-8 and gastrin-17 also augmented human and rodent β-cell proliferation and offered protection against streptozotocin-induced β-cell cytotoxicity. CONCLUSIONS We highlight the direct involvement of CCKA and CCKB receptors in pancreatic β-cell function and survival.
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Xia Q, Lu S, Ostrovsky J, McCormack SE, Falk MJ, Grant SFA. PARP-1 Inhibition Rescues Short Lifespan in Hyperglycemic C. Elegans And Improves GLP-1 Secretion in Human Cells. Aging Dis 2018; 9:17-30. [PMID: 29392078 PMCID: PMC5772855 DOI: 10.14336/ad.2017.0230] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 03/02/2017] [Indexed: 01/12/2023] Open
Abstract
TCF7L2 is located at one of the most strongly associated type 2 diabetes loci reported to date. We previously reported that the most abundant member of a specific protein complex to bind across the presumed causal variant at this locus, rs7903146, was poly [ADP-ribose] polymerase type 1 (PARP-1). We analyzed the impact of PARP-1 inhibition on C. elegans health in the setting of hyperglycemia and on glucose-stimulated GLP-1 secretion in human intestinal cells. Given that high glucose concentrations progressively shorten the lifespan of C. elegans, in part by impacting key well-conserved insulin-modulated signaling pathways, we investigated the effect of PARP-1 inhibition with Olaparib on the lifespan of C. elegans nematodes under varying hyperglycemic conditions. Subsequently, we investigated whether Olaparib treatment had any effect on glucose-stimulated GLP-1 secretion in the human NCI-H716 intestinal cell line, a model system for the investigation of enteroendocrine function. Treatment with 100uM Olaparib in nematodes exposed to high concentrations of glucose led to significant lifespan rescue. The beneficial lifespan effect of Olaparib appeared to require both PARP-1 and TCF7L2, since treatment had no effect in hyperglycemic conditions in knock-out worm strains for either of these homologs. Further investigation using the NCI-H716 cells revealed that Olaparib significantly enhanced secretion of the incretin, GLP-1, plus the gene expression of TCF7L2, GCG and PC1. These data from studies in both C. elegans and a human cell line suggest that PARP-1 inhibition offers a novel therapeutic avenue to treat type 2 diabetes.
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Affiliation(s)
- Qianghua Xia
- 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Sumei Lu
- 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Julian Ostrovsky
- 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Shana E McCormack
- 2Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,4Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Marni J Falk
- 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Struan F A Grant
- 1Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,2Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.,3Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,4Institute of Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
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Pathak NM, Millar PJB, Pathak V, Flatt PR, Gault VA. Beneficial metabolic effects of dietary epigallocatechin gallate alone and in combination with exendin-4 in high fat diabetic mice. Mol Cell Endocrinol 2018; 460:200-208. [PMID: 28754350 DOI: 10.1016/j.mce.2017.07.024] [Citation(s) in RCA: 7] [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: 02/10/2017] [Revised: 07/24/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Significant attempts are being made to generate multifunctional, hybrid or peptide combinations as novel therapeutic strategies for type 2 diabetes, however this presents key challenges including design and pharmaceutical development. In this study, we evaluated metabolic properties of oral nutritional supplement epigallocatechin gallate (EGCG) in combination with GLP-1 agonist exendin-4 in a mouse model of dietary-induced diabetes and obesity. METHODS EGCG, exendin-4 or combination of both were administered twice-daily over 28 days to high fat (HF) mice on background of low-dose streptozotocin. Energy intake, body weight, fat mass, glucose tolerance, insulin sensitivity, lipid profile, biochemical and hormone markers, and islet histology were examined. RESULTS All treatment groups exhibited significantly reduced body weight, fat mass, circulating glucose and insulin concentrations, and HbA1c levels which were independent of changes in energy intake. Similarly, there was marked improvement in glycaemic control, glucose-stimulated insulin release, insulin sensitivity, total cholesterol and triglycerides, with most prominent effects observed following combination therapy. Circulating corticosterone concentrations and 11beta-hydroxysteroid dehydrogenase type1 (11β-HSD1) staining (in pancreas) were beneficially decreased without changes in circulating interleukin 6 (IL-6), alanine transaminase (ALT) and glutathione reductase. Combination therapy resulted in increased islet area and number, beta cell area, and pancreatic insulin content. Generally, metabolic effects were much more pronounced in mice which received combination therapy. CONCLUSIONS EGCG alone and particularly in combination with exendin-4 exerts positive metabolic properties in HF mice. EGCG may be useful dietary adjunct alongside GLP-1 mimetics in treatment of diabetes and related disorders.
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Affiliation(s)
- Nupur M Pathak
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Paul J B Millar
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Varun Pathak
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Peter R Flatt
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom
| | - Victor A Gault
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
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Zhu M, Wei Y, Geißler C, Abschlag K, Corbalán Campos J, Hristov M, Möllmann J, Lehrke M, Karshovska E, Schober A. Hyperlipidemia-Induced MicroRNA-155-5p Improves β-Cell Function by Targeting Mafb. Diabetes 2017; 66:3072-3084. [PMID: 28970282 DOI: 10.2337/db17-0313] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 09/19/2017] [Indexed: 11/13/2022]
Abstract
A high-fat diet increases bacterial lipopolysaccharide (LPS) in the circulation and thereby stimulates glucagon-like peptide 1 (GLP-1)-mediated insulin secretion by upregulating interleukin-6 (IL-6). Although microRNA-155-5p (miR-155-5p), which increases IL-6 expression, is upregulated by LPS and hyperlipidemia and patients with familial hypercholesterolemia less frequently develop diabetes, the role of miR-155-5p in the islet stress response to hyperlipidemia is unclear. In this study, we demonstrate that hyperlipidemia-associated endotoxemia upregulates miR-155-5p in murine pancreatic β-cells, which improved glucose metabolism and the adaptation of β-cells to obesity-induced insulin resistance. This effect of miR-155-5p is because of suppression of v-maf musculoaponeurotic fibrosarcoma oncogene family, protein B, which promotes β-cell function through IL-6-induced GLP-1 production in α-cells. Moreover, reduced GLP-1 levels are associated with increased obesity progression, dyslipidemia, and atherosclerosis in hyperlipidemic Mir155 knockout mice. Hence, induction of miR-155-5p expression in β-cells by hyperlipidemia-associated endotoxemia improves the adaptation of β-cells to insulin resistance and represents a protective mechanism in the islet stress response.
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Affiliation(s)
- Mengyu Zhu
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Yuanyuan Wei
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Claudia Geißler
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Kathrin Abschlag
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Judit Corbalán Campos
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Michael Hristov
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Julia Möllmann
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
| | - Michael Lehrke
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
| | - Ela Karshovska
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
| | - Andreas Schober
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany
- German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance, Munich, Germany
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Natalicchio A, Marrano N, Biondi G, Spagnuolo R, Labarbuta R, Porreca I, Cignarelli A, Bugliani M, Marchetti P, Perrini S, Laviola L, Giorgino F. The Myokine Irisin Is Released in Response to Saturated Fatty Acids and Promotes Pancreatic β-Cell Survival and Insulin Secretion. Diabetes 2017; 66:2849-2856. [PMID: 28724742 DOI: 10.2337/db17-0002] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2017] [Accepted: 07/12/2017] [Indexed: 12/29/2022]
Abstract
This study explored the role of irisin as a new pancreatic β-cell secretagogue and survival factor and its potential role in the communication between skeletal muscle and pancreatic β-cells under lipotoxic conditions. Recombinant irisin stimulated insulin biosynthesis and glucose-stimulated insulin secretion (GSIS) in a PKA-dependent manner and prevented saturated fatty acid-induced apoptosis in human and rat pancreatic β-cells, as well as in human and murine pancreatic islets, via AKT/BCL2 signaling. Treatment of myotubes with 0.5 mmol/L palmitate for 4 h, but not with oleate, promoted an increase in irisin release in the culture medium. Moreover, increased serum levels of irisin were observed in mice fed with a high-fat diet. Mouse serum rich in irisin and the conditioned medium from myotubes exposed to palmitate for 4 h significantly reduced apoptosis of murine pancreatic islets and insulin-secreting INS-1E cells, respectively, and this was abrogated in the presence of an irisin-neutralizing antibody. Finally, in vivo administration of irisin improved GSIS and increased β-cell proliferation. In conclusion, irisin can promote β-cell survival and enhance GSIS and may thus participate in the communication between skeletal muscle and β-cells under conditions of excess saturated fatty acids.
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Affiliation(s)
- Annalisa Natalicchio
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Nicola Marrano
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppina Biondi
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Rosaria Spagnuolo
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Rossella Labarbuta
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Immacolata Porreca
- Istituto di Ricerche Genetiche "Gaetano Salvatore" (IRGS), Biogem, Ariano Irpino, Italy
| | - Angelo Cignarelli
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Bugliani
- Endocrinology and Metabolism of Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Piero Marchetti
- Endocrinology and Metabolism of Transplantation, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Sebastio Perrini
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Luigi Laviola
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Giorgino
- Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
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Kim DS, Choi HI, Wang Y, Luo Y, Hoffer BJ, Greig NH. A New Treatment Strategy for Parkinson's Disease through the Gut-Brain Axis: The Glucagon-Like Peptide-1 Receptor Pathway. Cell Transplant 2017; 26:1560-1571. [PMID: 29113464 PMCID: PMC5680957 DOI: 10.1177/0963689717721234] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 04/03/2017] [Indexed: 12/21/2022] Open
Abstract
Molecular communications in the gut-brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut-brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut-brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut-brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor.
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Affiliation(s)
- Dong Seok Kim
- Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
| | - Ho-Il Choi
- Peptron Inc., Yuseong-gu, Daejeon, Republic of Korea
| | - Yun Wang
- Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan
| | - Yu Luo
- Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Barry J. Hoffer
- Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Nigel H. Greig
- Drug Design and Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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Kapitza C, Dahl K, Jacobsen JB, Axelsen MB, Flint A. Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial. Diabetologia 2017; 60:1390-1399. [PMID: 28526920 PMCID: PMC5491562 DOI: 10.1007/s00125-017-4289-0] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 03/31/2017] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Semaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed. METHODS In this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18-64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5-9.0% (47.5-74.9 mmol/mol); BMI 20.0-35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0-10 min) and second (AUC10-120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed. RESULTS In total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0-10min and AUC10-120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0-24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated. CONCLUSIONS/INTERPRETATION Twelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes. TRIAL REGISTRATION ClinicalTrials.gov NCT02212067 FUNDING: The study was funded by Novo Nordisk A/S.
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Affiliation(s)
- Christoph Kapitza
- Profil Institut für Stoffwechselforschung GmbH, Hellersbergstrasse 9, 41460, Neuss, Germany.
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Meng X, Xu H, Zhang Z, Fawcett JP, Li J, Yang Y, Gu J. Differential mobility spectrometry tandem mass spectrometry with multiple ion monitoring for the bioanalysis of liraglutide. Anal Bioanal Chem 2017; 409:4885-4891. [DOI: 10.1007/s00216-017-0431-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 05/14/2017] [Accepted: 05/24/2017] [Indexed: 01/20/2023]
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Li C, Hou S, Liu S, Huan Y, Sun S, Liu Q, Shen Z. The albumin-exendin-4 recombinant protein E2HSA improves glycemic control and β-cell function in spontaneous diabetic KKAy mice. BMC Pharmacol Toxicol 2017. [PMID: 28629388 PMCID: PMC5477380 DOI: 10.1186/s40360-017-0143-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND E2HSA is a genetic fusion protein that consists of two tandem exendin-4 molecules that are covalently bonded to recombinant human serum albumin via a peptide linker. Previous studies have demonstrated that E2HSA significantly decreased blood glucose levels, improved β-cell function and promoted β-cell proliferation in diabetic db/dB mice. This study aimed to evaluate the benefits of E2HSA on glucose and lipid metabolism in a spontaneous diabetes animal model, KKAy mice. METHODS E2HSA was acutely administered at doses of 1, 3 and 9 mg/kg by subcutaneous injection in diabetic KKAy mice with exendin-4 (2 μg/kg) as a positive reference, and then the non-fasting blood glucose and food intake levels were dynamically monitored. In addition, different doses of E2HSA were injected once daily, as well as with exendin-4 twice daily, for 7 weeks to evaluate the effect on glucose and lipid metabolism, as well as the body weight, food and water intake. RESULTS Single injection of E2HSA decreased non-fasting blood glucose and food intake levels in a dose-dependent manner for 4 days and 2 days, respectively. Repeated injections with E2HSA significantly decreased variations in blood glucose levels with a reduction of HbA1c levels by 1.6% at a 9 mg/kg dose, simultaneously increased fasting blood insulin levels, inhibited fasting blood glucagon levels, improved the impaired oral glucose tolerance and enhanced glucose infusion rate, which is the gold standard for evaluating β-cell function. Moreover, repeated injections with E2HSA also ameliorated the dyslipidemia and reduced body weight, food and water intake in diabetic KKAy mice. CONCLUSIONS E2HSA significantly reduced blood glucose levels over a prolonged duration, enhanced β-cell function, and ameliorated dyslipidemia and obesity in diabetic KKAy mice. Thus, E2HSA may be a new candidate for the treatment of type 2 diabetes.
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Affiliation(s)
- Caina Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Shaocong Hou
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Shuainan Liu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Yi Huan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Sujuan Sun
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Quan Liu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China
| | - Zhufang Shen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Xiannongtan Street, Beijing, 100050, China.
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Cox AR, Lam CJ, Rankin MM, Rios JS, Chavez J, Bonnyman CW, King KB, Wells RA, Anthony D, Tu JX, Kim JJ, Li C, Kushner JA. Incretin Therapies Do Not Expand β-Cell Mass or Alter Pancreatic Histology in Young Male Mice. Endocrinology 2017; 158:1701-1714. [PMID: 28323942 PMCID: PMC5460937 DOI: 10.1210/en.2017-00027] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/02/2017] [Indexed: 12/28/2022]
Abstract
The impact of incretins upon pancreatic β-cell expansion remains extremely controversial. Multiple studies indicate that incretin-based therapies can increase β-cell proliferation, and incretins have been hypothesized to expand β-cell mass. However, disagreement exists on whether incretins increase β-cell mass. Moreover, some reports indicate that incretins may cause metaplastic changes in pancreatic histology. To resolve these questions, we treated a large cohort of mice with incretin-based therapies and carried out a rigorous analysis of β-cell turnover and pancreatic histology using high-throughput imaging. Young mice received exenatide via osmotic pump, des-fluoro-sitagliptin, or glipizide compounded in diet for 2 weeks (short-term) on a low-fat diet (LFD) or 4.5 months (long-term) on a LFD or high-fat diet (HFD). Pancreata were quantified for β-cell turnover and mass. Slides were examined for gross anatomical and microscopic changes to exocrine pancreas. Short-term des-fluoro-sitagliptin increased serum insulin and induced modest β-cell proliferation but no change in β-cell mass. Long-term incretin therapy in HFD-fed mice resulted in reduced weight gain, improved glucose homeostasis, and abrogated β-cell mass expansion. No evidence for rapidly dividing progenitor cells was found in islets or pancreatic parenchyma, indicating that incretins do not induce islet neogenesis or pancreatic metaplasia. Contrasting prior reports, we found no evidence of β-cell mass expansion after acute or chronic incretin therapy. Chronic incretin administration was not associated with histological abnormalities in pancreatic parenchyma; mice did not develop tumors, pancreatitis, or ductal hyperplasia. We conclude that incretin therapies do not generate β-cells or alter pancreatic histology in young mice.
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Affiliation(s)
- Aaron R. Cox
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Carol J. Lam
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Matthew M. Rankin
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Jacqueline S. Rios
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Julia Chavez
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Claire W. Bonnyman
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Kourtney B. King
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Roger A. Wells
- Department of Cellular, Molecular, and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824
- Consulting Tox/Path Services, Kittery, Maine 03904
| | - Deepti Anthony
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
| | - Justin X. Tu
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Jenny J. Kim
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Changhong Li
- Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104
| | - Jake A. Kushner
- McNair Medical Institute, Pediatric Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas 77030
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López M. EJE PRIZE 2017: Hypothalamic AMPK: a golden target against obesity? Eur J Endocrinol 2017; 176:R235-R246. [PMID: 28232370 PMCID: PMC5425938 DOI: 10.1530/eje-16-0927] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 01/26/2017] [Accepted: 02/22/2017] [Indexed: 12/16/2022]
Abstract
AMP-activated protein kinase (AMPK) is a cellular gauge that is activated under conditions, such as low energy, increasing energy production and reducing energy waste. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence links hypothalamic AMPK with feeding, brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), as well as muscle metabolism, hepatic function and glucose homeostasis. The relevance of these data is interesting from a therapeutic point of view as several agents with potential anti-obesity and/or antidiabetic effects, some currently in clinical use, such as nicotine, metformin and liraglutide are known to act through AMPK, either peripherally or centrally. Furthermore, the orexigenic and weight-gaining effects of the worldwide use of antipsychotic drugs (APDs), such as olanzapine, are also mediated by hypothalamic AMPK. Overall, this evidence makes hypothalamic AMPK signaling an interesting target for the drug development, with its potential for controlling both sides of the energy balance equation, namely feeding and energy expenditure through defined metabolic pathways.
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Affiliation(s)
- Miguel López
- Department of PhysiologyNeurObesity Group, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria and CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- Correspondence should be addressed to M López;
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López M, Tena-Sempere M. Estradiol effects on hypothalamic AMPK and BAT thermogenesis: A gateway for obesity treatment? Pharmacol Ther 2017; 178:109-122. [PMID: 28351720 DOI: 10.1016/j.pharmthera.2017.03.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 03/21/2017] [Indexed: 12/24/2022]
Abstract
In addition to their prominent roles in the control of reproduction, estrogens are important modulators of energy balance, as evident in conditions of deficiency of estrogens, which are characterized by increased feeding and decreased energy expenditure, leading to obesity. AMP-activated protein kinase (AMPK) is a ubiquitous cellular energy gauge that is activated under conditions of low energy, increasing energy production and reducing energy wasting. Centrally, the AMPK pathway is a canonical route regulating energy homeostasis, by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. As a result of those actions, hypothalamic AMPK modulates feeding, as well as brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). Here, we will review the central actions of estrogens on energy balance, with particular focus on hypothalamic AMPK. The relevance of this interaction is noteworthy, because some agents with known actions on metabolic homeostasis, such as nicotine, metformin, liraglutide, olanzapine and also natural molecules, such as resveratrol and flavonoids, exert their actions by modulating AMPK. This evidence highlights the possibility that hypothalamic AMPK might be a potential target for the treatment of obesity.
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Affiliation(s)
- Miguel López
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria (IDIS), 15782 Santiago de Compostela, Spain; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos II, Spain.
| | - Manuel Tena-Sempere
- CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos II, Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, 14004 Córdoba, Spain; FiDiPro Program, Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
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Li J, Su L, Gong YY, Ding ML, Hong SB, Yu S, Xiao HP. Downregulation of miR-139-5p contributes to the antiapoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1. PLoS One 2017; 12:e0173576. [PMID: 28346520 PMCID: PMC5367678 DOI: 10.1371/journal.pone.0173576] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 02/23/2017] [Indexed: 12/21/2022] Open
Abstract
Liraglutide is administered as glucagon-like peptide-1 (GLP-1) receptor agonist for diabetic patients and can protect pancreatic β-cells by inhibiting their apoptosis. MicroRNA-139-5p (miRNA-139-5p) participates in the regulation of cancer cell apoptosis. However, it is not clear whether miR-139-5p contributes to the anti-apoptotic effect of liraglutide in β-cells. The objective of the present study was to investigate the role of miR-139-5p on apoptosis of pancreatic β-cells. MicroRNA levels in pancreatic tissue from diabetic rats and INS-1 cells treated with liraglutide were measured by real-time quantitative RT-PCR. The role of miR-139-5p on apoptosis was studied by transfecting INS-1 cells with miR-139-5p mimics. The mRNA and protein expression of the target gene, insulin receptor substrate-1 (IRS1), were measured by qRT-PCR and Western blot, respectively. Apoptosis in rat pancreatic tissue and INS-1 cells was detected by TUNEL and annexin V/propidium iodide costaining. Apoptosis of pancreatic tissue from diabetic rats and INS-1 cells was decreased by administration of liraglutide. The expression of miR-139-5p increased in the pancreas of diabetic rats and decreased with liraglutide treatment. Incubation with liraglutide (100 nM) for 48 h attenuated the expression of miR-139-5p and increased the mRNA and protein levels of IRS1. Direct regulatory effects of miR-139-5p on IRS1 were found by a dual-luciferase reporter assay. Transfection of INS-1 cells with miR-139-5p mimics led to decreases in the mRNA and protein expression of IRS1. In conclusion, our observations suggest that decreased miR-139-5p expression contributes to the anti-apoptotic effect of liraglutide on the diabetic rat pancreas and INS-1 cells by targeting IRS1.
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Affiliation(s)
- Jin Li
- Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Lei Su
- Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Ying-ying Gong
- Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Mei-lin Ding
- Department of Geriatrics, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Shu-bin Hong
- Department of Endocrinology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Shuang Yu
- Department of Endocrinology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
| | - Hai-peng Xiao
- Department of Endocrinology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P.R. China
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Gilon P. Cocaine- and amphetamine-regulated transcript: a novel regulator of energy homeostasis expressed in a subpopulation of pancreatic islet cells. Diabetologia 2016; 59:1855-9. [PMID: 27421727 DOI: 10.1007/s00125-016-4052-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2016] [Accepted: 06/28/2016] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is characterised by chronic hyperglycaemia and its incidence is highly increased by exaggerated food consumption. It results from a lack of insulin action/production, but growing evidence suggests that it might also involve hyperglucagonaemia and impaired control of glucose homeostasis by the brain. In recent years, the cocaine and amphetamine-regulated transcript (CART) peptides have generated a lot of interest in the battle against obesity because, via the brain, they exert anorexic effects and they increase energy expenditure. They are also localised, outside the brain, in discrete regions of the body and play a hormonal role in controlling various functions. In this issue of Diabetologia, the Wierup group (doi: 10.1007/s00125-016-4020-6 ) shows that CART peptides are expressed heterogeneously in islet cells of various species, including humans, and that their expression is upregulated in diabetes. The authors also shine a spotlight on some interesting effects of CART peptides on islet function, including stimulation of insulin secretion and inhibition of glucagon release. CART peptides would thus be at the centre of a cooperation between the brain and the endocrine pancreas to control glucose homeostasis. Although the mechanisms of action of CART peptides remain enigmatic because no specific receptor for these peptides has so far been discovered, their potential therapeutic use is evident and represents a new challenge for future research.
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Affiliation(s)
- Patrick Gilon
- Pôle d'endocrinologie, diabète et nutrition, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Avenue Hippocrate 55, B1.55.06, 1200, Brussels, Belgium.
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Cantini G, Mannucci E, Luconi M. Perspectives in GLP-1 Research: New Targets, New Receptors. Trends Endocrinol Metab 2016; 27:427-438. [PMID: 27091492 DOI: 10.1016/j.tem.2016.03.017] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/27/2016] [Accepted: 03/30/2016] [Indexed: 02/06/2023]
Abstract
The incretin hormone glucagon-like peptide-1 (GLP-1) binds to and activates its G-protein-coupled-receptor GLP-1R to reduce glycaemia through the stimulation of insulin and suppression of pancreatic glucagon secretion. Recently, GLP-1 effects unrelated to glucose homeostasis have been discovered in myocardium, bone, adipose tissue, and other target organs, which appear to be mainly mediated by GLP-1R-independent pathways. Here, we summarize knowledge on GLP-1R agonists (GLP-1RAs) as they relate to the improvement of glucose control, and focus on the most recently described effects, discussing the preclinical evidence of the involvement of alternative receptors and signalling mechanisms. It is now evident that the universe of GLP-1RAs is expanding further from the initial incretin effect, opening new unforeseen avenues for research and clinical applications.
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Affiliation(s)
- Giulia Cantini
- Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy.
| | - Edoardo Mannucci
- Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy; Diabetes Agency, Careggi Hospital, Florence, Italy
| | - Michaela Luconi
- Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy.
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