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Yang M, Mandal K, Södergren M, Dumral Ö, Winroth L, Tengholm A. Real-time detection of somatostatin release from single islets reveals hypersecretion in type 2 diabetes. Acta Physiol (Oxf) 2025; 241:e14268. [PMID: 39803760 PMCID: PMC11726413 DOI: 10.1111/apha.14268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/01/2024] [Accepted: 01/01/2025] [Indexed: 01/16/2025]
Abstract
AIM Somatostatin from pancreatic δ-cells is a paracrine regulator of insulin and glucagon secretion, but the release kinetics and whether secretion is altered in diabetes is unclear. This study aimed to improve understanding of somatostatin secretion by developing a tool for real-time detection of somatostatin release from individual pancreatic islets. METHODS Reporter cells responding to somatostatin with cytoplasmic Ca2+ concentration ([Ca2+]i) changes were generated by co-expressing somatostatin receptor SSTR2, the G-protein Gα15 and a fluorescent Ca2+ sensor in HeLa cells. RESULTS Somatostatin induced dose-dependent [Ca2+]i increases in reporter cells with half-maximal and maximal effects at 1.6 ± 0.4 and ~30 nM, respectively. Mouse and human islets induced reporter cell [Ca2+]i elevations that were inhibited by the SSTR2 antagonist CYN154806. Depolarization of islets by high K+, KATP channel blockade or increasing the glucose concentration from 3 to 11 mM evoked concomitant elevations of [Ca2+]i in islets and reporter cells. Exposure of islets to glucagon, GLP-1 and ghrelin also triggered reporter cell [Ca2+]i responses, whereas little effect was obtained by islet exposure to insulin, glutamate, GABA and urocortin-3. Islets from type 2 diabetic human donors induced higher reporter cell [Ca2+]i responses at 11 mM and after K+ depolarization compared with non-diabetic islets, although fewer δ-cells were identified by immunostaining. CONCLUSION Type 2 diabetes is associated with hypersecretion of somatostatin, which has implications for paracrine regulation of insulin and glucagon secretion. The new reporter cell assay for real-time detection of single-islet somatostatin release holds promise for further studies of somatostatin secretion in islet physiology and pathophysiology.
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Affiliation(s)
- Mingyu Yang
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Kousik Mandal
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Moa Södergren
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Özge Dumral
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Lena Winroth
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
| | - Anders Tengholm
- Department of Medical Cell BiologyUppsala UniversityUppsalaSweden
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2
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Gupta D, Burstein AW, Shankar K, Varshney S, Singh O, Osborne-Lawrence S, Richard CP, Zigman JM. Impact of Ghrelin on Islet Size in Nonpregnant and Pregnant Female Mice. Endocrinology 2024; 165:bqae048. [PMID: 38626085 PMCID: PMC11075791 DOI: 10.1210/endocr/bqae048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/03/2024] [Accepted: 04/12/2024] [Indexed: 04/18/2024]
Abstract
Reducing ghrelin by ghrelin gene knockout (GKO), ghrelin-cell ablation, or high-fat diet feeding increases islet size and β-cell mass in male mice. Here we determined if reducing ghrelin also enlarges islets in females and if pregnancy-associated changes in islet size are related to reduced ghrelin. Islet size and β-cell mass were larger (P = .057 for β-cell mass) in female GKO mice. Pregnancy was associated with reduced ghrelin and increased liver-expressed antimicrobial peptide-2 (LEAP2; a ghrelin receptor antagonist) in wild-type mice. Ghrelin deletion and pregnancy each increased islet size (by ∼19.9-30.2% and ∼34.9-46.4%, respectively), percentage of large islets (>25 µm2×103, by ∼21.8-42% and ∼21.2-41.2%, respectively), and β-cell mass (by ∼15.7-23.8% and ∼65.2-76.8%, respectively). Neither islet cross-sectional area, β-cell cross-sectional area, nor β-cell mass correlated with plasma ghrelin, although all positively correlated with LEAP2 (P = .081 for islet cross-sectional area). In ad lib-fed mice, there was an effect of pregnancy, but not ghrelin deletion, to change (raise) plasma insulin without impacting blood glucose. Similarly, there was an effect of pregnancy, but not ghrelin deletion, to change (lower) blood glucose area under the curve during a glucose tolerance test. Thus, genetic deletion of ghrelin increases islet size and β-cell cross-sectional area in female mice, similar to males. Yet, despite pregnancy-associated reductions in ghrelin, other factors appear to govern islet enlargement and changes to insulin sensitivity and glucose tolerance in the setting of pregnancy. In the case of islet size and β-cell mass, one of those factors may be the pregnancy-associated increase in LEAP2.
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Affiliation(s)
- Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Avi W Burstein
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Corine P Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jeffrey M Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Division of Endocrinology & Metabolism, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX 75390, USA
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Kulkarni SS, Singh O, Zigman JM. The intersection between ghrelin, metabolism and circadian rhythms. Nat Rev Endocrinol 2024; 20:228-238. [PMID: 38123819 PMCID: PMC11760189 DOI: 10.1038/s41574-023-00927-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/16/2023] [Indexed: 12/23/2023]
Abstract
Despite the growing popular interest in sleep and diet, many gaps exist in our scientific understanding of the interaction between circadian rhythms and metabolism. In this Review, we explore a promising, bidirectional role for ghrelin in mediating this interaction. Ghrelin both influences and is influenced by central and peripheral circadian systems. Specifically, we focus on how ghrelin impacts outputs of circadian rhythm, including neuronal activity, circulating growth hormone levels, locomotor activity and eating behaviour. We also consider the effects of circadian rhythms on ghrelin expression and the consequences of disrupted circadian patterns, such as shift work and jet lag, on ghrelin secretion. Our Review is aimed at both the casual reader interested in gaining more insight into the scientific context surrounding the trending topics of sleep and metabolism, as well as experienced scientists in the fields of ghrelin and circadian biology seeking inspiration and a comprehensive overview of how these fields are related.
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Affiliation(s)
- Soumya S Kulkarni
- Medical Scientist Training Program, UT Southwestern Medical Center, Dallas, TX, USA
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey M Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
- Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA.
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, USA.
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Liu S, Zhu H, Ren Y, Fan W, Wu H, Wu H, Huang Z, Zhu W. A hydrolyzed casein diet promotes Ngn3 controlling enteroendocrine cell differentiation to increase gastrointestinal motility in mice. Food Funct 2024; 15:1237-1249. [PMID: 38227487 DOI: 10.1039/d3fo04152b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Gut hormones are produced by enteroendocrine cells (EECs) found along the intestinal epithelium, and these cells play a crucial role in regulating intestinal function, nutrient absorption and food intake. A hydrolyzed casein diet has been reported to promote the secretion of gut hormones through the regulation of EEC development, but the underlying mechanism remains unclear. Therefore, this study was conducted to investigate whether the hydrolyzed casein diet can regulate EEC differentiation by employing mouse and organoid models. Mice were fed diets containing either casein (casein group) or hydrolyzed casein (hydrolyzed casein group) as the sole protein source. The hydrolyzed casein diet upregulated the expression of transcription factors, induced EEC differentiation, increased fasting serum ghrelin concentrations and promoted gastrointestinal (GI) motility in the duodenum compared to the casein diet. Interestingly, these differences could be abolished when there is addition of antibiotics to the drinking water, suggesting a significant role of gut microbiota in the hydrolyzed casein-mediated EEC function. Further investigation showed that the hydrolyzed casein diet led to reduced microbial diversity, especially the abundance of Akkermansia muciniphila (A. muciniphila) on the duodenal mucosa. In contrast, gavage with A. muciniphila impaired EEC differentiation through attenuated neurog3 transcription factor (Ngn3) expression, mediated through the promotion of Notch signaling. Moreover, pasteurized A. muciniphila showed similar effects to enter organoids in vitro. Overall, we found that a hydrolyzed casein diet reduced the abundance of A. muciniphila and promoted Ngn3 controlling EEC differentiation and this pathway is associated with increased GI motility in mice. The findings provide new insights into the role of hydrolyzed casein in gut transit and guidelines for using hydrolyzed casein in safe formula milk.
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Affiliation(s)
- Siqiang Liu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Haining Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Yuting Ren
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Wenlu Fan
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Huipeng Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Zan Huang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
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Gupta D, Burstein AW, Schwalbe DC, Shankar K, Varshney S, Singh O, Paul S, Ogden SB, Osborne-Lawrence S, Metzger NP, Richard CP, Campbell JN, Zigman JM. Ghrelin deletion and conditional ghrelin cell ablation increase pancreatic islet size in mice. J Clin Invest 2023; 133:e169349. [PMID: 38099492 PMCID: PMC10721155 DOI: 10.1172/jci169349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 10/05/2023] [Indexed: 12/18/2023] Open
Abstract
Ghrelin exerts key effects on islet hormone secretion to regulate blood glucose levels. Here, we sought to determine whether ghrelin's effects on islets extend to the alteration of islet size and β cell mass. We demonstrate that reducing ghrelin - by ghrelin gene knockout (GKO), conditional ghrelin cell ablation, or high-fat diet (HFD) feeding - was associated with increased mean islet size (up to 62%), percentage of large islets (up to 854%), and β cell cross-sectional area (up to 51%). In GKO mice, these effects were more apparent in 10- to 12-week-old mice than in 4-week-old mice. Higher β cell numbers from decreased β cell apoptosis drove the increase in β cell cross-sectional area. Conditional ghrelin cell ablation in adult mice increased the β cell number per islet by 40% within 4 weeks. A negative correlation between islet size and plasma ghrelin in HFD-fed plus chow-fed WT mice, together with even larger islet sizes in HFD-fed GKO mice than in HFD-fed WT mice, suggests that reduced ghrelin was not solely responsible for diet-induced obesity-associated islet enlargement. Single-cell transcriptomics revealed changes in gene expression in several GKO islet cell types, including upregulation of Manf, Dnajc3, and Gnas expression in β cells, which supports decreased β cell apoptosis and/or increased β cell proliferation. These effects of ghrelin reduction on islet morphology might prove useful when designing new therapies for diabetes.
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Affiliation(s)
- Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Avi W. Burstein
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Dana C. Schwalbe
- Department of Biology, University of Virginia, Charlottesville, Virginia, USA
| | - Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Subhojit Paul
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sean B. Ogden
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Nathan P. Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corine P. Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - John N. Campbell
- Department of Biology, University of Virginia, Charlottesville, Virginia, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Division of Endocrinology and Metabolism, Department of Internal Medicine and
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
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6
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Toren E, Kepple JD, Coutinho KV, Poole SO, Deeba IM, Pierre TH, Liu Y, Bethea MM, Hunter CS. The SSBP3 co-regulator is required for glucose homeostasis, pancreatic islet architecture, and beta-cell identity. Mol Metab 2023; 76:101785. [PMID: 37536498 PMCID: PMC10448474 DOI: 10.1016/j.molmet.2023.101785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/24/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023] Open
Abstract
OBJECTIVE Transcriptional complex activity drives the development and function of pancreatic islet cells to allow for proper glucose regulation. Prior studies from our lab and others highlighted that the LIM-homeodomain transcription factor (TF), Islet-1 (Isl1), and its interacting co-regulator, Ldb1, are vital effectors of developing and adult β-cells. We further found that a member of the Single Stranded DNA-Binding Protein (SSBP) co-regulator family, SSBP3, interacts with Isl1 and Ldb1 in β-cells and primary islets (mouse and human) to impact β-cell target genes MafA and Glp1R in vitro. Members of the SSBP family stabilize TF complexes by binding directly to Ldb1 and protecting the complex from ubiquitin-mediated turnover. In this study, we hypothesized that SSBP3 has critical roles in pancreatic islet cell function in vivo, similar to the Isl1::Ldb1 complex. METHODS We first developed a novel SSBP3 LoxP allele mouse line, where Cre-mediated recombination imparts a predicted early protein termination. We bred this mouse with constitutive Cre lines (Pdx1- and Pax6-driven) to recombine SSBP3 in the developing pancreas and islet (SSBP3ΔPanc and SSBP3ΔIslet), respectively. We assessed glucose tolerance and used immunofluorescence to detect changes in islet cell abundance and markers of β-cell identity and function. Using an inducible Cre system, we also deleted SSBP3 in the adult β-cell, a model termed SSBP3Δβ-cell. We measured glucose tolerance as well as glucose-stimulated insulin secretion (GSIS), both in vivo and in isolated islets in vitro. Using islets from control and SSBP3Δβ-cell we conducted RNA-Seq and compared our results to published datasets for similar β-cell specific Ldb1 and Isl1 knockouts to identify commonly regulated target genes. RESULTS SSBP3ΔPanc and SSBP3ΔIslet neonates present with hyperglycemia. SSBP3ΔIslet mice are glucose intolerant by P21 and exhibit a reduction of β-cell maturity markers MafA, Pdx1, and UCN3. We observe disruptions in islet cell architecture with an increase in glucagon+ α-cells and ghrelin+ ε-cells at P10. Inducible loss of β-cell SSBP3 in SSBP3Δβ-cell causes hyperglycemia, glucose intolerance, and reduced GSIS. Transcriptomic analysis of 14-week-old SSBP3Δβ-cell islets revealed a decrease in β-cell function gene expression (Ins, MafA, Ucn3), increased stress and dedifferentiation markers (Neurogenin-3, Aldh1a3, Gastrin), and shared differentially expressed genes between SSBP3, Ldb1, and Isl1 in adult β-cells. CONCLUSIONS SSBP3 drives proper islet identity and function, where its loss causes altered islet-cell abundance and glucose homeostasis. β-Cell SSBP3 is required for GSIS and glucose homeostasis, at least partially through shared regulation of Ldb1 and Isl1 target genes.
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Affiliation(s)
- Eliana Toren
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Jessica D Kepple
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Kristen V Coutinho
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Samuel O Poole
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Iztiba M Deeba
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Tanya H Pierre
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Yanping Liu
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Maigen M Bethea
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Chad S Hunter
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
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Kehagias D, Georgopoulos N, Habeos I, Lampropoulos C, Mulita F, Kehagias I. The role of the gastric fundus in glycemic control. Hormones (Athens) 2023; 22:151-163. [PMID: 36705877 DOI: 10.1007/s42000-023-00429-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 01/10/2023] [Indexed: 01/28/2023]
Abstract
PURPOSE Ghrelin, one of the most studied gut hormones, is mainly produced by the gastric fundus. Abundant evidence exists from preclinical and clinical studies underlining its contribution to glucose regulation. In the following narrative review, the role of the gastric fundus in glucose regulation is summarized and we investigate whether its resection enhances glycemic control. METHODS An electronic search was conducted in the PubMed® database and in Google Scholar® using a combination of medical subject headings (MeSH). We examined types of metabolic surgery, including, in particular, gastric fundus resection, either as part of laparoscopic sleeve gastrectomy (LSG) or modified laparoscopic gastric bypass with fundus resection (LRYGBP + FR), and the contribution of ghrelin reduction to glucose regulation. RESULTS Fourteen human studies were judged to be eligible and included in this narrative review. Reduction of ghrelin levels after fundus resection might be related to early glycemic improvement before significant weight loss is achieved. Long-term data regarding the role of ghrelin reduction in glucose homeostasis are sparse. CONCLUSION The exact role of ghrelin in achieving glycemic control is still ambiguous. Data from human studies reveal a potential contribution of ghrelin reduction to early glycemic improvement, although further well-designed studies are needed.
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Affiliation(s)
- Dimitrios Kehagias
- Department of General Surgery, General University Hospital of Patras, 26504, Rio, Greece.
| | - Neoklis Georgopoulos
- Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Patras Medical School, 26504, Rio, Greece
| | - Ioannis Habeos
- Division of Endocrinology and Diabetes, Department of Internal Medicine, University Hospital of Patras, 26504, Rio, Greece
| | | | - Francesk Mulita
- Department of General Surgery, General University Hospital of Patras, 26504, Rio, Greece
| | - Ioannis Kehagias
- Division of Bariatric and Metabolic Surgery, Department of Surgery, General University Hospital of Patras, 26504, Rio, Greece
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Kosiukhno S, Usenko O, Todurov I, Plehutsa О. CHANGE OF GHRELIN CONCENTRATION IN TYPE 2 DIABETES MELLITUS ASSOCIATED WITH OBESITY IN THE EARLY AND DELAYED PERIOD AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY. FIZIOLOHICHNYĬ ZHURNAL 2023; 69:50-59. [DOI: 10.15407/fz69.03.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Laparoscopic sleeve gastrectomy (LSG) is an effective method of treating obesity complicated by type 2 diabetes mellitus (T2DM). The performance of this metabolic surgical intervention involves removal fundus of the stomach, which in turn leads to an effect on the eating behavior of patients in the form of a decrease in appetite and loss of excess body weight with a parallel effect on the compensation of T2DM in the postoperative period, regardless of the loss of body weight. At present, mechanisms of T2DM compensation after LSG have not yet been clearly defined. The aim of our study was to study the effect of LSG on the dynamics of changes in the blood plasma ghrelin levels in patients with T2DM associated with obesity. The plasma ghrelin levels were assessed in the fasted state, 15, 30, 60, and 90 min after a standard breakfast carbohydrate preload, which included 125 ml of Nutricia Nutridrink, a balanced high-energy protein. The examination was carried out before the operation, on the 4th postoperative day and 3 months after the operation. 7 patients were diagnosed with T2DM for the first time, 3 had a history of diabetes for 2 years, one patient had a history of 3.5 years, and another had a history of 10 years. The average content of glycated hemoglobin before the operation was 7.7%, 3 months after LSG - 5.9%. The fasting ghrelin concentration before LSG performing was 6.8 ng/ml, on the 4th postoperative day – 4.6 ng/ml, and 3 months after the operation – 4.4 ng/ml (P = 0.001) in comparison with preoperative indicators). The peak insulin concentration was noted 30 min after the carbohydrate preload 3 months after the operation and was 175.1 μU/ml, and its fasting levels in the postoperative period reached a statistically significant difference compared to the preoperative values (30 μU/ml before surgery and 25.3 μU/ml 3 months after LSG). Thus, LSG leads to an early and significant suppression of fasting ghrelin secretion in patients with obesity-associated T2DM and likely to restore insulin secretion and/or reduce insulin resistance. Rapid postoperative improvement of carbohydrate metabolism components indicates the importance of the early reduction of ghrelin secretion in combination with the incretin effect of LSG in the implementation of the mechanisms of early compensation of T2DM and explains the metabolic activity of this operation and the significant role of the stomach in the regulation of glucose metabolism.
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Eliasson L, Wierup N. Editorial: Special issue novel aspects of islet peptides. Peptides 2022; 157:170879. [PMID: 36150630 DOI: 10.1016/j.peptides.2022.170879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Affiliation(s)
- Lena Eliasson
- Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Clinical Research Centre, Skåne University Hospital (SUS), Jan Waldenströms gata 35, Malmö 21428, Sweden.
| | - Nils Wierup
- Lund University Diabetes Centre, Department of Clinical Sciences Malmö, Clinical Research Centre, Skåne University Hospital (SUS), Jan Waldenströms gata 35, Malmö 21428, Sweden.
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Abstract
Islet dysfunction is central in type 2 diabetes and full-blown type 2 diabetes develops first when the beta cells lose their ability to secrete adequate amounts of insulin in response to raised plasma glucose. Several mechanisms behind beta cell dysfunction have been put forward but many important questions still remain. Furthermore, our understanding of the contribution of each islet cell type in type 2 diabetes pathophysiology has been limited by technical boundaries. Closing this knowledge gap will lead to a leap forward in our understanding of the islet as an organ and potentially lead to improved treatments. The development of single-cell RNA sequencing (scRNAseq) has led to a breakthrough for characterising the transcriptome of each islet cell type and several important observations on the regulation of cell-type-specific gene expression have been made. When it comes to identifying type 2 diabetes disease mechanisms, the outcome is still limited. Several studies have identified differentially expressed genes, although there is very limited consensus between the studies. As with all new techniques, scRNAseq has limitations; in addition to being extremely expensive, genes expressed at low levels may not be detected, noise may not be appropriately filtered and selection biases for certain cell types are at hand. Furthermore, recent advances suggest that commonly used computational tools may be suboptimal for analysis of scRNAseq data in small-scale studies. Fortunately, development of new computational tools holds promise for harnessing the full potential of scRNAseq data. Here we summarise how scRNAseq has contributed to increasing the understanding of various aspects of islet biology as well as type 2 diabetes disease mechanisms. We also focus on challenges that remain and propose steps to promote the utilisation of the full potential of scRNAseq in this area.
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Affiliation(s)
| | - Nils Wierup
- Lund University Diabetes Centre, Malmö, Sweden.
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Zhang X, Cheng Z, Dong S, Rayner C, Wu T, Zhong M, Zhang G, Wang K, Hu S. Effects of ileal glucose infusion on enteropancreatic hormone secretion in humans: relationship to glucose absorption. Metabolism 2022; 131:155198. [PMID: 35395220 DOI: 10.1016/j.metabol.2022.155198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/13/2022] [Accepted: 03/28/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUNDS The distal small intestine plays an important role in regulating the secretion of entero-pancreatic hormones that are critical to the control of glucose metabolism and appetite, but the quantitative contribution of a specific segment to these effects is unknown. PURPOSES To determine the effects of 30 cm of the ileum exposed to glucose on the secretion of ghrelin, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) insulin, C-peptide and glucagon, in relation to glucose absorption in non-diabetic subjects. BASIC PROCEDURES 10 non-diabetic subjects with a loop ileostomy after early-stage rectal cancer resection were studied on 2 days in a double-blind, randomized and crossover fashion, when a catheter was inserted retrogradely 30 cm from the ileostomy for infusion of a glucose solution containing 30 g glucose and 3 g 3-O-methylglucose (as a marker of active glucose absorption), or 0.9% saline, over 60 min. Ghrelin, GIP, GLP-1, insulin, C-peptide, glucagon and ileal glucose absorption (from concentrations of 3-O-methylglucose in serum and glucose in ileostomy effluent) were measured over 180 min. MAIN FINDINGS 12.0 ± 1.2 g glucose was absorbed over 180 min. Compared to saline, ileal glucose resulted in minimal increases in blood glucose and plasma insulin and C-peptide, but substantial increases in plasma GLP-1, without affecting ghrelin, GIP or glucagon. The magnitude of the GLP-1 response to glucose was strongly related to the increase in serum 3-O-methylglucose. PRINCIPAL CONCLUSIONS Stimulation of the terminal ileum by glucose, even over a short length (30 cm), induces substantial GLP-1 release, coupled primarily to active glucose absorption. CLINICAL REGISTRATION NCT05030376 (ClinicalTrials.gov).
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Affiliation(s)
- Xiang Zhang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Zhiqiang Cheng
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Shuohui Dong
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
| | - Christopher Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, SA, Australia
| | - Mingwei Zhong
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China
| | - Guangyong Zhang
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China
| | - Kexin Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, China.
| | - Sanyuan Hu
- Department of General Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong Province, China; Shandong University, China.
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12
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Khan D, Moffett RC, Flatt PR, Tarasov AI. Classical and non-classical islet peptides in the control of β-cell function. Peptides 2022; 150:170715. [PMID: 34958851 DOI: 10.1016/j.peptides.2021.170715] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/25/2021] [Accepted: 12/17/2021] [Indexed: 12/25/2022]
Abstract
The dual role of the pancreas as both an endocrine and exocrine gland is vital for food digestion and control of nutrient metabolism. The exocrine pancreas secretes enzymes into the small intestine aiding digestion of sugars and fats, whereas the endocrine pancreas secretes a cocktail of hormones into the blood, which is responsible for blood glucose control and regulation of carbohydrate, protein and fat metabolism. Classical islet hormones, insulin, glucagon, pancreatic polypeptide and somatostatin, interact in an autocrine and paracrine manner, to fine-tube the islet function and insulin secretion to the needs of the body. Recently pancreatic islets have been reported to express a number of non-classical peptide hormones involved in metabolic signalling, whose major production site was believed to reside outside pancreas, e.g. in the small intestine. We highlight the key non-classical islet peptides, and consider their involvement, together with established islet hormones, in regulation of stimulus-secretion coupling as well as proliferation, survival and transdifferentiation of β-cells. We furthermore focus on the paracrine interaction between classical and non-classical islet hormones in the maintenance of β-cell function. Understanding the functional relationships between these islet peptides might help to develop novel, more efficient treatments for diabetes and related metabolic disorders.
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Affiliation(s)
- Dawood Khan
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK.
| | - R Charlotte Moffett
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Peter R Flatt
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
| | - Andrei I Tarasov
- Biomedical Sciences Research Institute, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland, UK
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13
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Hucik B, Lovell AJ, Hoecht EM, Cervone DT, Mutch DM, Dyck DJ. Regulation of adipose tissue lipolysis by ghrelin is impaired with high-fat diet feeding and is not restored with exercise. Adipocyte 2021; 10:338-349. [PMID: 34224298 PMCID: PMC8259717 DOI: 10.1080/21623945.2021.1945787] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Ghrelin is released from the stomach as an anticipatory signal prior to a meal and decreases immediately after. Previous research has shown that both acylated (AG) and unacylated (UnAG) ghrelin blunt adrenoreceptor-stimulated lipolysis in rat white adipose tissue (WAT) ex vivo. We investigated whether acute or chronic consumption of a high fat diet (HFD) impaired the ability of ghrelin to regulate adipose tissue lipolysis, and if this impairment could be restored with exercise. After 5 days (5d) of a HFD, or 6 weeks (6 w) of a HFD (60% kcal from fat) with or without exercise training, inguinal and retroperitoneal WAT was collected from anesthetized rats for adipose tissue organ culture. Samples were treated with 1 μM CL 316,243 (CL; lipolytic control), 1 μM CL+150 ng/ml AG or 1 μM CL+150 ng/ml UnAG. Incubation media and tissue were collected after 2 hours. Colorometric assays were used to determine glycerol and free fatty acid (FFA) concentrations in media. Western blots were used to quantify the protein content of lipolytic enzymes and ghrelin receptors in both depots. CL stimulated lipolysis was evidenced by increases in glycerol (p < 0.0001) and FFA (p < 0.0001) concentrations in media compared to control. AG decreased CL-stimulated glycerol release in inguinal WAT from 5d LFD rats (p = 0.0097). Neither AG nor UnAG blunted lipolysis in adipose tissue from 5d or 6 w HFD-fed rats, and exercise did not restore ghrelin’s anti-lipolytic ability in 6 w HFD-fed rats. Overall, this study demonstrates that HFD consumption impairs ghrelin’s ability to regulate adipose tissue lipolysis.
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Affiliation(s)
- Barbora Hucik
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Andrew J. Lovell
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Evan M. Hoecht
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Daniel T. Cervone
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - David M. Mutch
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - David J. Dyck
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
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14
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Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System. Int J Mol Sci 2021; 22:ijms221910571. [PMID: 34638910 PMCID: PMC8509076 DOI: 10.3390/ijms221910571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 01/19/2023] Open
Abstract
Ghrelin is an endogenous ligand for the ghrelin receptor, previously known as the growth hormone secretagogue receptor. This hormone is mainly produced by endocrine cells present in the gastric mucosa. The ghrelin-producing cells are also present in other organs of the body, mainly in the digestive system, but in much smaller amount. Ghrelin exhibits a broad spectrum of physiological effects, such as stimulation of growth hormone secretion, gastric secretion, gastrointestinal motility, and food intake, as well as regulation of glucose homeostasis and bone formation, and inhibition of inflammatory processes. This review summarizes the recent findings concerning animal and human data showing protective and therapeutic effects of ghrelin in the gut, and also presents the role of growth hormone and insulin-like growth factor-1 in these effects. In addition, the current data on the possible influence of ghrelin on the carcinogenesis, its importance in predicting the risk of developing gastrointestinal malignances, as well as the potential usefulness of ghrelin in the treatment of cancer, have been presented.
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15
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Lee YS, Song GJ, Jun HS. Betacellulin-Induced α-Cell Proliferation Is Mediated by ErbB3 and ErbB4, and May Contribute to β-Cell Regeneration. Front Cell Dev Biol 2021; 8:605110. [PMID: 33553143 PMCID: PMC7859283 DOI: 10.3389/fcell.2020.605110] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 12/15/2020] [Indexed: 11/15/2022] Open
Abstract
Betacellulin (BTC), an epidermal growth factor family, is known to promote β-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new β-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and β-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new β-cells.
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Affiliation(s)
- Young-Sun Lee
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.,Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, South Korea.,Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, South Korea
| | - Gyun Jee Song
- Department of Medical Science, College of Medicine, Catholic Kwandong University, Gangneung, South Korea.,Translational Brain Research Center, International St. Mary's Hospital, Catholic Kwandong University, Incheon, South Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, South Korea.,College of Pharmacy, Gachon University, Incheon, South Korea.,Gachon Medical and Convergence Institute, Gachon Gil Medical Center, Incheon, South Korea
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16
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Henquin JC. Paracrine and autocrine control of insulin secretion in human islets: evidence and pending questions. Am J Physiol Endocrinol Metab 2021; 320:E78-E86. [PMID: 33103455 DOI: 10.1152/ajpendo.00485.2020] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Insulin secretion by β-cells is largely controlled by circulating nutrients, hormones, and neurotransmitters. However, recent years have witnessed the multiplication of studies investigating whether local regulation also takes place within pancreatic islets, in which β-cells cohabit with several other cell types. The cell composition and architectural organization of human islets differ from those of rodent islets and are particularly favorable to cellular interactions. An impressive number of hormonal (glucagon, glucagon-like peptide-1, somatostatin, etc.) and nonhormonal products (ATP, acetylcholine, γ-aminobutyric acid, dopamine, etc.) are released by islet cells and have been implicated in a local control of insulin secretion. This review analyzes reports directly testing paracrine and autocrine control of insulin secretion in isolated human islets. Many of these studies were designed on background information collected in rodent islets. However, the perspective of the review is not to highlight species similarities or specificities but to contrast established and speculative mechanisms in human islets. It will be shown that the current evidence is convincing only for a minority of candidates for a paracrine function whereas arguments supporting a physiological role of others do not stand up to scrutiny. Several pending questions await further investigation.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium
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17
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Félix-Martínez GJ, N. Mata A, Godínez-Fernández JR. Reconstructing human pancreatic islet architectures using computational optimization. Islets 2020; 12:121-133. [PMID: 33090076 PMCID: PMC7751670 DOI: 10.1080/19382014.2020.1823178] [Citation(s) in RCA: 5] [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] [Indexed: 12/30/2022] Open
Abstract
We outline a general methodology based on computational optimization and experimental data to reconstruct human pancreatic islet architectures. By using the nuclei coordinates of islet cells obtained through DAPI staining, cell types identified by immunostaining, and cell size distributions estimated from capacitance measurements, reconstructed islets composed of non-overlapping spherical cells were obtained through an iterative optimization procedure. In all cases, the reconstructed architectures included >99% of the experimental identified cells, each of them having a radius within the experimentally reported ranges. Given the wide use of mathematical modeling for the study of pancreatic cells, and recently, of cell-cell interactions within the pancreatic islets, the methodology here proposed, also capable of identifying cell-to-cell contacts, is aimed to provide with a framework for modeling and analyzing experimentally-based pancreatic islet architectures.
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Affiliation(s)
- Gerardo J. Félix-Martínez
- Cátedras CONACYT, Consejo Nacional de Ciencia y Tecnología, Mexico City, México
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Mexico City, México
- CONTACT Gerardo J. Félix-Martínez Laboratory of Biophysics AT-221, Universidad Autónoma Metropolitana; San Rafael Atlixco 186, Col. Vicentina, 09340, Iztalapapa, CDMX, México
| | - Aurelio N. Mata
- Department of Electrical Engineering, Universidad Autónoma Metropolitana, Mexico City, México
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18
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Gupta S, Mitra A. Heal the heart through gut (hormone) ghrelin: a potential player to combat heart failure. Heart Fail Rev 2020; 26:417-435. [PMID: 33025414 DOI: 10.1007/s10741-020-10032-2] [Citation(s) in RCA: 5] [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] [Accepted: 09/21/2020] [Indexed: 12/17/2022]
Abstract
Ghrelin, a small peptide hormone (28 aa), secreted mainly by X/A-like cells of gastric mucosa, is also locally produced in cardiomyocytes. Being an orexigenic factor (appetite stimulant), it promotes release of growth hormone (GH) and exerts diverse physiological functions, viz. regulation of energy balance, glucose, and/or fat metabolism for body weight maintenance. Interestingly, administration of exogenous ghrelin significantly improves cardiac functions in CVD patients as well as experimental animal models of heart failure. Ghrelin ameliorates pathophysiological condition of the heart in myocardial infarction, cardiac hypertrophy, fibrosis, cachexia, and ischemia reperfusion injury. This peptide also exerts significant impact at the level of vasculature leading to lowering high blood pressure and reversal of endothelial dysfunction and atherosclerosis. However, the molecular mechanism of actions elucidating the healing effects of ghrelin on the cardiovascular system is still a matter of conjecture. Some experimental data indicate its beneficial effects via complex cellular cross talks between autonomic nervous system and cardiovascular cells, some other suggest more direct receptor-mediated molecular actions via autophagy or ionotropic regulation and interfering with apoptotic and inflammatory pathways of cardiomyocytes and vascular endothelial cells. Here, in this review, we summarise available recent data to encourage more research to find the missing links of unknown ghrelin receptor-mediated pathways as we see ghrelin as a future novel therapy in cardiovascular protection.
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Affiliation(s)
- Shreyasi Gupta
- Department of Zoology, Triveni Devi Bhalotia College, Raniganj, Paschim Bardhaman, 713347, India
| | - Arkadeep Mitra
- Department of Zoology, City College , 102/1, Raja Rammohan Sarani, Kolkata, 700009, India.
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19
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Lindqvist A, Shcherbina L, Prasad RB, Miskelly MG, Abels M, Martínez-Lopéz JA, Fred RG, Nergård BJ, Hedenbro J, Groop L, Hjerling-Leffler J, Wierup N. Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels. Mol Cell Endocrinol 2020; 511:110835. [PMID: 32371087 DOI: 10.1016/j.mce.2020.110835] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/07/2020] [Accepted: 04/21/2020] [Indexed: 01/22/2023]
Abstract
It is not known how ghrelin affects insulin secretion in human islets from patients with type 2 diabetes (T2D) or whether islet ghrelin expression or circulating ghrelin levels are altered in T2D. Here we sought out to identify the effect of ghrelin on insulin secretion in human islets and the impact of T2D on circulating ghrelin levels and on islet ghrelin cells. The effect of ghrelin on insulin secretion was assessed in human T2D and non-T2D islets. Ghrelin expression was assessed with RNA-sequencing (n = 191) and immunohistochemistry (n = 21). Plasma ghrelin was measured with ELISA in 40 T2D and 40 non-T2D subjects. Ghrelin exerted a glucose-dependent insulin-suppressing effect in islets from both T2D and non-T2D donors. Compared with non-T2D donors, T2D donors had reduced ghrelin mRNA expression and 75% less islet ghrelin cells, and ghrelin mRNA expression correlated negatively with HbA1c. T2D subjects had 25% lower fasting plasma ghrelin levels than matched controls. Thus, ghrelin has direct insulin-suppressing effects in human islets and T2D patients have lower fasting ghrelin levels, likely as a result of reduced number of islet ghrelin cells. These findings support inhibition of ghrelin signaling as a potential therapeutic avenue for stimulation of insulin secretion in T2D patients.
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Affiliation(s)
- A Lindqvist
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - L Shcherbina
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - R B Prasad
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - M G Miskelly
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - M Abels
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - J A Martínez-Lopéz
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - R G Fred
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | | | - J Hedenbro
- Lund University Diabetes Centre, Lund University, Malmö, Sweden; Aleris Obesitas, Lund, Sweden
| | - L Groop
- Lund University Diabetes Centre, Lund University, Malmö, Sweden; Finnish Institute of Molecular Medicine, Helsinki, Finland
| | - J Hjerling-Leffler
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - N Wierup
- Lund University Diabetes Centre, Lund University, Malmö, Sweden.
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20
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Gray SM, Niu J, Zhang A, Svendsen B, Campbell JE, D'Alessio DA, Tong J. Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice. Diabetes 2019; 68:1795-1805. [PMID: 31201280 PMCID: PMC6702634 DOI: 10.2337/db19-0079] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 06/06/2019] [Indexed: 01/08/2023]
Abstract
Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intraislet ghrelin-GHSR axis modulates insulin secretion and glucose metabolism using mouse models lacking ghrelin (Ghrl-/- ) or GHSR (Ghsr-/- ). Ghsr-/- and Ghsr+/+ mice had comparable islet ghrelin concentrations. Exogenous ghrelin decreased insulin secretion in perifused isolated islets in a GHSR-dependent manner. Islets isolated from Ghrl-/- or Ghsr-/- mice did not differ from controls in glucose-, alanine-, or GLP-1-stimulated insulin secretion during perifusion. Consistent with this finding, Ghrl-/- and Ghsr-/- male mice studied after either 6 or 16 h of fasting had blood glucose concentrations comparable with those of controls following intraperitoneal glucose, or insulin tolerance tests, or after mixed nutrient meals. Collectively, our data provide strong evidence against a paracrine ghrelin-GHSR axis mediating insulin secretion or glucose tolerance in lean, chow-fed adult mice.
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Affiliation(s)
| | | | | | | | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Durham, NC
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Durham, NC
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
| | - Jenny Tong
- Duke Molecular Physiology Institute, Durham, NC
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
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21
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Gray SM, Page LC, Tong J. Ghrelin regulation of glucose metabolism. J Neuroendocrinol 2019; 31:e12705. [PMID: 30849212 PMCID: PMC6688917 DOI: 10.1111/jne.12705] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate.
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Affiliation(s)
- Sarah. M. Gray
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
| | - Laura C. Page
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
| | - Jenny Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC 27701
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22
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Abstract
The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.
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Affiliation(s)
- Carl Johan Drott
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Petra Franzén
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
- Department of Medical Sciences, Uppsala University , Uppsala , Sweden
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23
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Mani BK, Shankar K, Zigman JM. Ghrelin's Relationship to Blood Glucose. Endocrinology 2019; 160:1247-1261. [PMID: 30874792 PMCID: PMC6482034 DOI: 10.1210/en.2019-00074] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/09/2019] [Indexed: 12/16/2022]
Abstract
Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food reward, body weight, adiposity, and energy expenditure. Although endogenous ghrelin's actions on some of these processes remain ambiguous, its glucoregulatory actions have emerged as well-recognized features during extreme metabolic conditions. The blood glucose-raising actions of ghrelin are beneficial during starvation-like conditions, defending against life-threatening falls in blood glucose, but they are seemingly detrimental in obese states and in certain monogenic forms of diabetes, contributing to hyperglycemia. Also of interest, blood glucose negatively regulates ghrelin secretion. This article reviews the literature suggesting the existence of a blood glucose-ghrelin axis and highlights the factors that mediate the glucoregulatory actions of ghrelin, especially during metabolic extremes such as starvation and diabetes.
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Affiliation(s)
- Bharath K Mani
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kripa Shankar
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey M Zigman
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
- Correspondence: Jeffrey M. Zigman, MD, PhD, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390. E-mail:
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Jansson L, Carlsson PO. Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans. Compr Physiol 2019; 9:799-837. [PMID: 30892693 DOI: 10.1002/cphy.c160050] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5- to 10-fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo-acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799-837, 2019.
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Affiliation(s)
- Leif Jansson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden
| | - Per-Ola Carlsson
- Uppsala University, Department of Medical Cell Biology, Uppsala, Sweden.,Uppsala University, Department of Medical Sciences, Uppsala, Sweden
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25
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Small BC, Quiniou SM, Kaiya H, Bledsoe JW, Musungu B. Characterization of a third ghrelin receptor, GHS-R3a, in channel catfish reveals novel expression patterns and a high affinity for homologous ligand. Comp Biochem Physiol A Mol Integr Physiol 2019; 229:1-9. [DOI: 10.1016/j.cbpa.2018.11.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 11/16/2018] [Accepted: 11/18/2018] [Indexed: 11/30/2022]
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26
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Dominguez Gutierrez G, Kim J, Lee AH, Tong J, Niu J, Gray SM, Wei Y, Ding Y, Ni M, Adler C, Murphy AJ, Gromada J, Xin Y. Gene Signature of the Human Pancreatic ε Cell. Endocrinology 2018; 159:4023-4032. [PMID: 30380031 PMCID: PMC6963699 DOI: 10.1210/en.2018-00833] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 10/17/2018] [Indexed: 12/31/2022]
Abstract
The ghrelin-producing ε cell represents the fifth endocrine cell type in human pancreatic islets. The abundance of ε cells in adult pancreas is extremely low, which has hampered the investigation on the molecular pathways regulating the development and the function of this cell type. In this study, we explored the molecular features defining the function of pancreatic ε cells isolated from adult nondiabetic donors using single-cell RNA sequencing technology. We focus on transcription factors, cell surface receptors, and genes involved in metabolic pathways that contribute to regulation of cellular function. Furthermore, the genes that separate ε cells from the other islet endocrine cell types are presented. This study expands prior knowledge about the genes important for ε cell functioning during development and provides a resource to interrogate the transcriptome of this rare human islet cell type.
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Affiliation(s)
| | - Jinrang Kim
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Ann-Hwee Lee
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Jenny Tong
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - JingJing Niu
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Sarah M Gray
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Yi Wei
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Yueming Ding
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Min Ni
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | | | | | - Yurong Xin
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
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27
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Neuroendocrinology of Adipose Tissue and Gut-Brain Axis. ADVANCES IN NEUROBIOLOGY 2018; 19:49-70. [PMID: 28933061 DOI: 10.1007/978-3-319-63260-5_3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Food intake and energy expenditure are closely regulated by several mechanisms which involve peripheral organs and nervous system, in order to maintain energy homeostasis.Short-term and long-term signals express the size and composition of ingested nutrients and the amount of body fat, respectively. Ingested nutrients trigger mechanical forces and gastrointestinal peptide secretion which provide signals to the brain through neuronal and endocrine pathways. Pancreatic hormones also play a role in energy balance exerting a short-acting control regulating the start, end, and composition of a meal. In addition, insulin and leptin derived from adipose tissue are involved in long-acting adiposity signals and regulate body weigh as well as the amount of energy stored as fat over time.This chapter focuses on the gastrointestinal-, pancreatic-, and adipose tissue-derived signals which are integrated in selective orexigenic and anorexigenic brain areas that, in turn, regulate food intake, energy expenditure, and peripheral metabolism.
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Abstract
Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
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Affiliation(s)
- Gabriela Da Silva Xavier
- Section of Functional Genomics and Cell Biology, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston B15 2TT, UK.
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29
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Mohan S, Khan D, Moffett RC, Irwin N, Flatt PR. Oxytocin is present in islets and plays a role in beta-cell function and survival. Peptides 2018; 100:260-268. [PMID: 29274352 DOI: 10.1016/j.peptides.2017.12.019] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 01/18/2023]
Abstract
Oxytocin is associated mainly with modulating reproductive function. However, studies suggest that oxytocin also plays a role in endocrine pancreatic function. In the present study, islet expression of oxytocin and its related receptor was confirmed in mouse islets as well as cultured rodent and human beta-cells. Oxytocin significantly stimulated glucose-induced insulin secretion from isolated mouse islets. Similar insulinotropic actions were also observed in rodent BRIN BD11 and human 1.1B4 beta-cells. Positive effects of oxytocin on insulin secretion were almost fully annulled by the oxytocin receptor antagonist, atosiban. In terms of mechanism of insulin secretory action, oxytocin had no effect on beta-cell membrane potential or cAMP generation, but did augment intracellular calcium concentrations. In vivo administration of oxytocin to mice significantly reduced overall blood glucose levels and increased plasma insulin concentrations in response to a glucose challenge. Oxytocin also had a modest, but significant, appetite suppressive effect. As expected, streptozotocin diabetic mice had marked loss of beta-cell area accompanied by increases in alpha-cell area, whilst hydrocortisone treatment increased beta-cell and overall islet areas. Both mouse models of diabetes presented with dramatically decreased percentage islet oxytocin co-localisation with insulin and increased co-localisation with glucagon. More detailed studies in cultured beta-cell lines revealed direct positive effects of oxytocin on beta-cell proliferation and protection against apoptosis. Together, these data highlight a potentially important role of islet-derived oxytocin and related receptor signalling pathways on the modulation of beta-cell function and survival.
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Affiliation(s)
- Shruti Mohan
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Dawood Khan
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
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30
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Tan BL, Norhaizan ME, Liew WPP. Nutrients and Oxidative Stress: Friend or Foe? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:9719584. [PMID: 29643982 PMCID: PMC5831951 DOI: 10.1155/2018/9719584] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 11/24/2017] [Accepted: 12/04/2017] [Indexed: 02/07/2023]
Abstract
There are different types of nutritionally mediated oxidative stress sources that trigger inflammation. Much information indicates that high intakes of macronutrients can promote oxidative stress and subsequently contribute to inflammation via nuclear factor-kappa B- (NF-κB-) mediated cell signaling pathways. Dietary carbohydrates, animal-based proteins, and fats are important to highlight here because they may contribute to the long-term consequences of nutritionally mediated inflammation. Oxidative stress is a central player of metabolic ailments associated with high-carbohydrate and animal-based protein diets and excessive fat consumption. Obesity has become an epidemic and represents the major risk factor for several chronic diseases, including diabetes, cardiovascular disease (CVD), and cancer. However, the molecular mechanisms of nutritionally mediated oxidative stress are complex and poorly understood. Therefore, this review aimed to explore how dietary choices exacerbate or dampen the oxidative stress and inflammation. We also discussed the implications of oxidative stress in the adipocyte and glucose metabolism and obesity-associated noncommunicable diseases (NCDs). Taken together, a better understanding of the role of oxidative stress in obesity and the development of obesity-related NCDs would provide a useful approach. This is because oxidative stress can be mediated by both extrinsic and intrinsic factors, hence providing a plausible means for the prevention of metabolic disorders.
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Affiliation(s)
- Bee Ling Tan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Mohd Esa Norhaizan
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
- Research Centre of Excellent, Nutrition and Non-Communicable Diseases (NNCD), Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
| | - Winnie-Pui-Pui Liew
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia
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31
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Castiello FR, Tabrizian M. Multiplex Surface Plasmon Resonance Imaging-Based Biosensor for Human Pancreatic Islets Hormones Quantification. Anal Chem 2018; 90:3132-3139. [DOI: 10.1021/acs.analchem.7b04288] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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32
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Paternoster S, Falasca M. Dissecting the Physiology and Pathophysiology of Glucagon-Like Peptide-1. Front Endocrinol (Lausanne) 2018; 9:584. [PMID: 30364192 PMCID: PMC6193070 DOI: 10.3389/fendo.2018.00584] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Accepted: 09/14/2018] [Indexed: 12/11/2022] Open
Abstract
An aging world population exposed to a sedentary life style is currently plagued by chronic metabolic diseases, such as type-2 diabetes, that are spreading worldwide at an unprecedented rate. One of the most promising pharmacological approaches for the management of type 2 diabetes takes advantage of the peptide hormone glucagon-like peptide-1 (GLP-1) under the form of protease resistant mimetics, and DPP-IV inhibitors. Despite the improved quality of life, long-term treatments with these new classes of drugs are riddled with serious and life-threatening side-effects, with no overall cure of the disease. New evidence is shedding more light over the complex physiology of GLP-1 in health and metabolic diseases. Herein, we discuss the most recent advancements in the biology of gut receptors known to induce the secretion of GLP-1, to bridge the multiple gaps into our understanding of its physiology and pathology.
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33
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Rorsman P, Ashcroft FM. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev 2018; 98:117-214. [PMID: 29212789 PMCID: PMC5866358 DOI: 10.1152/physrev.00008.2017] [Citation(s) in RCA: 517] [Impact Index Per Article: 73.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/30/2017] [Accepted: 06/18/2017] [Indexed: 12/14/2022] Open
Abstract
The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM.
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Affiliation(s)
- Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Department of Neuroscience and Physiology, Metabolic Research Unit, Göteborg, Sweden; and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Frances M Ashcroft
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Department of Neuroscience and Physiology, Metabolic Research Unit, Göteborg, Sweden; and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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34
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Mani BK, Zigman JM. Ghrelin as a Survival Hormone. Trends Endocrinol Metab 2017; 28:843-854. [PMID: 29097101 PMCID: PMC5777178 DOI: 10.1016/j.tem.2017.10.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 10/03/2017] [Accepted: 10/05/2017] [Indexed: 12/22/2022]
Abstract
Ghrelin administration induces food intake and body weight gain. Based on these actions, the ghrelin system was initially proposed as an antiobesity target. Subsequent studies using genetic mouse models have raised doubts about the role of the endogenous ghrelin system in mediating body weight homeostasis or obesity. However, this is not to say that the endogenous ghrelin system is not important metabolically or otherwise. Here we review an emerging concept in which the endogenous ghrelin system serves an essential function during extreme nutritional and psychological challenges to defend blood glucose, protect body weight, avoid exaggerated depression, and ultimately allow survival.
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Affiliation(s)
- Bharath K Mani
- Divisions of Hypothalamic Research and Endocrinology, Department of Internal Medicine, and Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9077, USA
| | - Jeffrey M Zigman
- Divisions of Hypothalamic Research and Endocrinology, Department of Internal Medicine, and Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9077, USA.
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35
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Effects of Ghrelin miRNA on Inflammation and Calcium Pathway in Pancreatic Acinar Cells of Acute Pancreatitis. Pancreas 2017; 46:1305-1313. [PMID: 28984792 DOI: 10.1097/mpa.0000000000000946] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The study investigated the effects of endogenous targeted inhibition of ghrelin gene on inflammation and calcium pathway in an in vitro pancreatic acinar cell model of acute pancreatitis. METHODS Lentiviral expression vector against ghrelin gene was constructed and transfected into AR42J cells. The mRNA and protein expression of each gene were detected by reverse transcription polymerase chain reaction, Western blotting, or enzyme-linked immunosorbent assay. The concentration of intracellular calcium ([Ca]i) was determined by calcium fluorescence mark probe combined with laser scanning confocal microscopy. RESULTS Compared with the control group, cerulein could upregulate mRNA and protein expression of inflammatory factors, calcium pathway, ghrelin, and [Ca]i. mRNA and protein expression of inflammatory factors increased significantly in cells transfected with ghrelin miRNA compared with the other groups. Intracellular calcium and expression of some calcium pathway proteins decreased significantly in cells transfected with ghrelin miRNA compared with the other groups. CONCLUSIONS Targeted inhibition of ghrelin gene in pancreatic acinar cells of acute pancreatitis can upregulate the expression of the intracellular inflammatory factors and alleviate the intracellular calcium overload.
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36
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Hetherington AM, Sawyez CG, Sutherland BG, Robson DL, Arya R, Kelly K, Jacobs RL, Borradaile NM. Treatment with didemnin B, an elongation factor 1A inhibitor, improves hepatic lipotoxicity in obese mice. Physiol Rep 2017; 4:4/17/e12963. [PMID: 27613825 PMCID: PMC5027364 DOI: 10.14814/phy2.12963] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Eukaryotic elongation factor EEF1A1 is induced by oxidative and ER stress, and contributes to subsequent cell death in many cell types, including hepatocytes. We recently showed that blocking the protein synthesis activity of EEF1A1 with the peptide inhibitor, didemnin B, decreases saturated fatty acid overload-induced cell death in HepG2 cells. In light of this and other recent work suggesting that limiting protein synthesis may be beneficial in treating ER stress-related disease, we hypothesized that acute intervention with didemnin B would decrease hepatic ER stress and lipotoxicity in obese mice with nonalcoholic fatty liver disease (NAFLD). Hyperphagic male ob/ob mice were fed semipurified diet for 4 weeks, and during week 5 received i.p. injections of didemnin B or vehicle on days 1, 4, and 7. Interestingly, we observed that administration of this compound modestly decreased food intake without evidence of illness or distress, and thus included an additional control group matched for food consumption with didemnin B-treated animals. Treatment with didemnin B improved several characteristics of hepatic lipotoxicity to a greater extent than the effects of caloric restriction alone, including hepatic steatosis, and some hepatic markers of ER stress and inflammation (GRP78, Xbp1s, and Mcp1). Plasma lipid and lipoprotein profiles and histopathological measures of NAFLD, including lobular inflammation, and total NAFLD activity score were also improved by didemnin B. These data indicate that acute intervention with the EEF1A inhibitor, didemnin B, improves hepatic lipotoxicity in obese mice with NAFLD through mechanisms not entirely dependent on decreased food intake, suggesting a potential therapeutic strategy for this ER stress-related disease.
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Affiliation(s)
- Alexandra M Hetherington
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Cynthia G Sawyez
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada Department of Medicine, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Brian G Sutherland
- Robarts Research Institute, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Debra L Robson
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Rigya Arya
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
| | - Karen Kelly
- Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - René L Jacobs
- Metabolic and Cardiovascular Diseases Laboratory, Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada
| | - Nica M Borradaile
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry Western University, London, Ontario, Canada
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37
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Wang JX, Li P, Zhang XT, Ye LX. Distribution and developmental changes of ghrelin-immunopositive cells in the pancreas of African ostrich chicks (Struthio camelus). Poult Sci 2017; 96:3445-3451. [PMID: 28595319 DOI: 10.3382/ps/pex145] [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: 01/26/2017] [Accepted: 05/14/2017] [Indexed: 11/20/2022] Open
Abstract
Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by multiple cell types and affects feeding behavior, metabolic regulation, and energy balance. In the mammalian pancreas, the types of endocrine cells that are immunoreactive to ghrelin vary. However, little was known about its distribution and developmental changes in the pancreas of African ostrich chicks (Struthio camelus). In the present study, the distribution, morphological characteristics, and developmental changes of ghrelin-immunopositive (ghrelin-ip) cells in the pancreas of African ostrich chicks were investigated using immunohistochemistry. Ghrelin-ip cells were found in both the pancreatic islets and acinar cell regions. The greatest number of ghrelin-ip cells were found in the pancreatic islets, and were primarily observed at the periphery of the islets; some ghrelin-ip cells were also located in the central portion of the pancreatic islets. Interestingly, from postnatal d 1 to d 90, there was a steady decrease in the number of ghrelin-ip cells in the pancreatic islets and acinar cell regions. These results clearly demonstrated that ghrelin-ip cells exist and decreased with age in the African ostrich pancreas from postnatal d 1 to d90. Thus, these findings indicated that ghrelin may be involved in the development of the pancreas in the African ostrich.
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Affiliation(s)
- J X Wang
- College of Animal Science, Yangtze University, Jingzhou 434103, P. R. China; Ostrich Research Institute, Yangtze University, Jingzhou 434103, P. R. China.
| | - P Li
- College of Animal Science, Yangtze University, Jingzhou 434103, P. R. China; Ostrich Research Institute, Yangtze University, Jingzhou 434103, P. R. China
| | - X T Zhang
- College of Animal Science, Yangtze University, Jingzhou 434103, P. R. China; Ostrich Research Institute, Yangtze University, Jingzhou 434103, P. R. China
| | - L X Ye
- College of Animal Science, Yangtze University, Jingzhou 434103, P. R. China; Ostrich Research Institute, Yangtze University, Jingzhou 434103, P. R. China
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Arous C, Wehrle-Haller B. Role and impact of the extracellular matrix on integrin-mediated pancreatic β-cell functions. Biol Cell 2017; 109:223-237. [PMID: 28266044 DOI: 10.1111/boc.201600076] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 12/17/2022]
Abstract
Understanding the organisation and role of the extracellular matrix (ECM) in islets of Langerhans is critical for maintaining pancreatic β-cells, and to recognise and revert the physiopathology of diabetes. Indeed, integrin-mediated adhesion signalling in response to the pancreatic ECM plays crucial roles in β-cell survival and insulin secretion, two major functions, which are affected in diabetes. Here, we would like to present an update on the major components of the pancreatic ECM, their role during integrin-mediated cell-matrix adhesions and how they are affected during diabetes. To treat diabetes, a promising approach consists in replacing β-cells by transplantation. However, efficiency is low, because β-cells suffer of anoikis, due to enzymatic digestion of the pancreatic ECM, which affects the survival of insulin-secreting β-cells. The strategy of adding ECM components during transplantation, to reproduce the pancreatic microenvironment, is a challenging task, as many of the regulatory mechanisms that control ECM deposition and turnover are not sufficiently understood. A better comprehension of the impact of the ECM on the adhesion and integrin-dependent signalling in β-cells is primordial to improve the healthy state of islets to prevent the onset of diabetes as well as for enhancing the efficiency of the islet transplantation therapy.
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Affiliation(s)
- Caroline Arous
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
| | - Bernhard Wehrle-Haller
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
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39
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Kruszelnicka O, Kuźma M, Pena IZ, Perera IB, Chyrchel B, Wieczorek-Surdacka E, Surdacki A. No Association of Proton Pump Inhibitor Use with Fasting or Postload Glycaemia in Patients with Cardiovascular Disease: A Cross-Sectional Retrospective Study. Int J Med Sci 2017; 14:1015-1021. [PMID: 28924374 PMCID: PMC5599926 DOI: 10.7150/ijms.19457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Accepted: 06/20/2017] [Indexed: 12/23/2022] Open
Abstract
Background: Proton pump inhibitor (PPI) use was reportedly associated with an excess of adverse cardiovascular (CV) events, thus making their systemic effects relevant to public health. PPIs reduce gastric acid secretion, causing increased gastrin release. Gastrin stimulates β-cell neogenesis and enhances insulin release, exerting an incretin-like effect. Our aim was to assess, if PPI usage is associated with altered glycaemia in patients with CV disease. Methods: We retrospectively analyzed medical records of 102 subjects (80 with ischemic heart disease) who underwent a routine oral glucose tolerance test while hospitalized in a cardiology department. Fasting and 2-h postload glucose levels were compared according to PPI use for ≥1 month prior to admission. Results: Compared to 51 subjects without PPIs, those on a PPI were older, more frequently male, had a lower body-mass index and a tendency to a worse renal function. PPI users and non-users exhibited similar glucose levels at baseline (5.6 ± 0.9 vs. 5.5 ± 1.1 mmol/l, P = 0.5) and 2-hrs post glucose intake (9.8 ± 3.0 vs. 9.9 ± 3.4 mmol/l, P = 0.9). This was consistent across subgroups stratified by gender or diabetes status. The results were substantially unchanged after adjustment for different characteristics of subjects with and without PPIs. Conclusions: PPI use does not appear associated with altered glycaemia in subjects with CV disease. Unchanged glucose tolerance despite PPI usage may result from simultaneous activation of pathways that counteract the putative PPI-induced incretin-like effect.
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Affiliation(s)
- Olga Kruszelnicka
- Department of Coronary Artery Disease and Heart Failure, John Paul II Hospital, Cracow, Poland
| | - Marcin Kuźma
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Iwona Z Pena
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Ian B Perera
- Students' Scientific Group at the Second Department of Cardiology, School of Medicine in English, Jagiellonian University Medical College, Cracow, Poland
| | - Bernadeta Chyrchel
- Second Department of Cardiology, Jagiellonian University Medical College, Cracow, Poland
| | | | - Andrzej Surdacki
- Second Department of Cardiology, Jagiellonian University Medical College, Cracow, Poland
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40
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Khan D, Vasu S, Moffett RC, Irwin N, Flatt PR. Islet distribution of Peptide YY and its regulatory role in primary mouse islets and immortalised rodent and human beta-cell function and survival. Mol Cell Endocrinol 2016; 436:102-13. [PMID: 27465830 DOI: 10.1016/j.mce.2016.07.020] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Revised: 07/18/2016] [Accepted: 07/19/2016] [Indexed: 12/25/2022]
Abstract
Recent evidence suggests that the classic gut peptide, Peptide YY (PYY), could play a fundamental role in endocrine pancreatic function. In the present study expression of PYY and its NPY receptors on mouse islets and immortalised rodent and human beta-cells was examined together with the effects of both major circulating forms of PYY, namely PYY(1-36) and PYY(3-36), on beta-cell function, murine islet adaptions to insulin deficiency/resistance, as well as direct effects on cultured beta-cell proliferation and apoptosis. In vivo administration of PYY(3-36), but not PYY(1-36), markedly (p < 0.05) decreased food intake in overnight fasted mice. Neither form of PYY affected glucose disposal or insulin secretion following an i.p. glucose challenge. However, in vitro, PYY(1-36) and PYY(3-36) inhibited (p < 0.05 to p < 0.001) glucose, alanine and GLP-1 stimulated insulin secretion from immortalised rodent and human beta-cells, as well as isolated mouse islets, by impeding alterations in membrane potential, [Ca(2+)]i and elevations of cAMP. Mice treated with multiple low dose streptozotocin presented with severe (p < 0.01) loss of beta-cell mass accompanied by notable increases (p < 0.001) in alpha and PP cell numbers. In contrast, hydrocortisone-induced insulin resistance increased islet number (p < 0.01) and beta-cell mass (p < 0.001). PYY expression was consistently observed in alpha-, PP- and delta-, but not beta-cells. Streptozotocin decreased islet PYY co-localisation with PP (p < 0.05) and somatostatin (p < 0.001), whilst hydrocortisone increased PYY co-localisation with glucagon (p < 0.05) in mice. More detailed in vitro investigations revealed that both forms of PYY augmented (p < 0.05 to p < 0.01) immortalised human and rodent beta-cell proliferation and protected against streptozotocin-induced cytotoxicity, to a similar or superior extent as the well characterised beta-cell proliferative and anti-apoptotic agent GLP-1. Taken together, these data highlight the significance and potential offered by modulation of pancreatic islet NPY receptor signalling pathways for preservation of beta-cell mass in diabetes.
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Affiliation(s)
- Dawood Khan
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Srividya Vasu
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - R Charlotte Moffett
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
| | - Nigel Irwin
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
| | - Peter R Flatt
- SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK
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41
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Adriaenssens AE, Svendsen B, Lam BYH, Yeo GSH, Holst JJ, Reimann F, Gribble FM. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia 2016; 59:2156-65. [PMID: 27390011 PMCID: PMC5016554 DOI: 10.1007/s00125-016-4033-1] [Citation(s) in RCA: 160] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 06/01/2016] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Intra-islet and gut-islet crosstalk are critical in orchestrating basal and postprandial metabolism. The aim of this study was to identify regulatory proteins and receptors underlying somatostatin secretion though the use of transcriptomic comparison of purified murine alpha, beta and delta cells. METHODS Sst-Cre mice crossed with fluorescent reporters were used to identify delta cells, while Glu-Venus (with Venus reported under the control of the Glu [also known as Gcg] promoter) mice were used to identify alpha and beta cells. Alpha, beta and delta cells were purified using flow cytometry and analysed by RNA sequencing. The role of the ghrelin receptor was validated by imaging delta cell calcium concentrations using islets with delta cell restricted expression of the calcium reporter GCaMP3, and in perfused mouse pancreases. RESULTS A database was constructed of all genes expressed in alpha, beta and delta cells. The gene encoding the ghrelin receptor, Ghsr, was highlighted as being highly expressed and enriched in delta cells. Activation of the ghrelin receptor raised cytosolic calcium levels in primary pancreatic delta cells and enhanced somatostatin secretion in perfused pancreases, correlating with a decrease in insulin and glucagon release. The inhibition of insulin secretion by ghrelin was prevented by somatostatin receptor antagonism. CONCLUSIONS/INTERPRETATION Our transcriptomic database of genes expressed in the principal islet cell populations will facilitate rational drug design to target specific islet cell types. The present study indicates that ghrelin acts specifically on delta cells within pancreatic islets to elicit somatostatin secretion, which in turn inhibits insulin and glucagon release. This highlights a potential role for ghrelin in the control of glucose metabolism.
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Affiliation(s)
- Alice E Adriaenssens
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Berit Svendsen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Brian Y H Lam
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Giles S H Yeo
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Jens J Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Frank Reimann
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
| | - Fiona M Gribble
- Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
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Mani BK, Osborne-Lawrence S, Vijayaraghavan P, Hepler C, Zigman JM. β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals. J Clin Invest 2016; 126:3467-78. [PMID: 27548523 DOI: 10.1172/jci86270] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 07/07/2016] [Indexed: 01/06/2023] Open
Abstract
Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction-associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell-expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker-associated hypoglycemia in susceptible individuals, such as young children.
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43
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Tong J, Mauvais-Jarvis F. The D-Day of ghrelin. Mol Metab 2016; 5:433-434. [PMID: 27408768 PMCID: PMC4921939 DOI: 10.1016/j.molmet.2016.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 05/11/2016] [Indexed: 11/29/2022] Open
Affiliation(s)
- Jenny Tong
- Division of Endocrinology, Department of Medicine, Duke Molecular and Physiology Institute, Duke University, Durham, NC, USA.
| | - Franck Mauvais-Jarvis
- Division of Endocrinology and Metabolism, Department of Medicine and Pharmacology, Tulane University Health Sciences Center, New Orleans, LA, USA
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44
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Jiang FX, Morahan G. Insulin-secreting β cells require a post-genomic concept. World J Diabetes 2016; 7:198-208. [PMID: 27226815 PMCID: PMC4873311 DOI: 10.4239/wjd.v7.i10.198] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 03/18/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic insulin-secreting β cells are essential in maintaining normal glucose homeostasis accomplished by highly specialized transcription of insulin gene, of which occupies up to 40% their transcriptome. Deficiency of these cells causes diabetes mellitus, a global public health problem. Although tremendous endeavors have been made to generate insulin-secreting cells from human pluripotent stem cells (i.e., primitive cells capable of giving rise to all cell types in the body), a regenerative therapy to diabetes has not yet been established. Furthermore, the nomenclature of β cells has become inconsistent, confusing and controversial due to the lack of standardized positive controls of developmental stage-matched in vivo cells. In order to minimize this negative impact and facilitate critical research in this field, a post-genomic concept of pancreatic β cells might be helpful. In this review article, we will briefly describe how β cells were discovered and islet lineage is developed that may help understand the cause of nomenclatural controversy, suggest a post-genomic definition and finally provide a conclusive remark on future research of this pivotal cell.
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45
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Kim HS, Lee MK. β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas. J Diabetes Investig 2016; 7:286-96. [PMID: 27330712 PMCID: PMC4847880 DOI: 10.1111/jdi.12475] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 12/27/2015] [Accepted: 01/04/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β‐cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β‐cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin‐producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β‐cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β‐cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin‐producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin‐producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin‐producing cells, especially duct and acinar cells.
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Affiliation(s)
- Hyo-Sup Kim
- Division of Endocrinology and Metabolism Department of Medicine Sungkyunkwan University School of Medicine Samsung Biomedical Research Institute Samsung Medical Center Seoul Korea
| | - Moon-Kyu Lee
- Division of Endocrinology and Metabolism Department of Medicine Sungkyunkwan University School of Medicine Samsung Biomedical Research Institute Samsung Medical Center Seoul Korea
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46
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Zhao Y, Zhang X, Chen J, Lin C, Shao R, Yan C, Chen C. Hexarelin Protects Rodent Pancreatic Β-Cells Function from Cytotoxic Effects of Streptozotocin Involving Mitochondrial Signalling Pathways In Vivo and In Vitro. PLoS One 2016; 11:e0149730. [PMID: 26918825 PMCID: PMC4769129 DOI: 10.1371/journal.pone.0149730] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 02/04/2016] [Indexed: 01/25/2023] Open
Abstract
Mitochondrial functions are crucial for pancreatic β-cell survival and glucose-induced insulin secretion. Hexarelin (Hex) is a synthetic small peptide ghrelin analogue, which has been shown to protect cardiomyocytes from the ischemia-reperfusion process. In this study, we used in vitro and in vivo models of streptozotocin (STZ)-induced β-cell damage to study the protective effect of Hex and the associated mechanisms. We found that STZ produced a cytotoxic effect in a dose- and time-dependent manner in MIN6 cells (a mouse β-cell line). Hex (1.0 μM) decreased the STZ-induced damage in β-cells. Rhodamine 123 assay and superoxide DHE production assay revealed that Hex ameliorated STZ-induced mitochondrial damage and excessive superoxide activity in β-cells. In addition, Hex significantly reduced STZ-induced expression of cleaved Caspases-3, Caspases-9 and the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2 in MIN6 cells. We further examined the in vivo effect of Hex in a rat model of type 1 diabetes induced by STZ injection. Hex ameliorated STZ-induced decrease in plasma insulin and protected the structure of islets from STZ-induced disruption. Hex also ameliorated STZ-induced expression of cleaved Caspase-9 and the Bax in β-cells. In conclusion, our data indicate that Hex is able to protects β-cell mass from STZ-caused cytotoxic effects involving mitochondrial pathways in vitro and in vivo. Hex may serve as a potential protective agent for the management of diabetes.
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Affiliation(s)
- Yan Zhao
- Institute of Basic Medicine Science, Xi'an Medical University, Xi'an, China
- Department of Forensic Science, School of Medicine, Xi’an Jiaotong University, Xi’an, China
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Xinli Zhang
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Jiezhong Chen
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Chao Lin
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
| | - Renfu Shao
- Gene Cology Research Centre, Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Maroochydore, QLD, Australia
| | - Chunxia Yan
- Department of Forensic Science, School of Medicine, Xi’an Jiaotong University, Xi’an, China
| | - Chen Chen
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD, Australia
- * E-mail:
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47
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Castiello FR, Heileman K, Tabrizian M. Microfluidic perfusion systems for secretion fingerprint analysis of pancreatic islets: applications, challenges and opportunities. LAB ON A CHIP 2016; 16:409-31. [PMID: 26732665 DOI: 10.1039/c5lc01046b] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2023]
Abstract
A secretome signature is a heterogeneous profile of secretions present in a single cell type. From the secretome signature a smaller panel of proteins, namely a secretion fingerprint, can be chosen to feasibly monitor specific cellular activity. Based on a thorough appraisal of the literature, this review explores the possibility of defining and using a secretion fingerprint to gauge the functionality of pancreatic islets of Langerhans. It covers the state of the art regarding microfluidic perfusion systems used in pancreatic islet research. Candidate analytical tools to be integrated within microfluidic perfusion systems for dynamic secretory fingerprint monitoring were identified. These analytical tools include patch clamp, amperometry/voltametry, impedance spectroscopy, field effect transistors and surface plasmon resonance. Coupled with these tools, microfluidic devices can ultimately find applications in determining islet quality for transplantation, islet regeneration and drug screening of therapeutic agents for the treatment of diabetes.
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Affiliation(s)
- F Rafael Castiello
- Biomedical Engineering Department, McGill University, Montreal, QC H3A 2B4, Canada.
| | - Khalil Heileman
- Biomedical Engineering Department, McGill University, Montreal, QC H3A 2B4, Canada.
| | - Maryam Tabrizian
- Biomedical Engineering Department, McGill University, Montreal, QC H3A 2B4, Canada.
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48
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Wiedemann T, Bielohuby M, Müller TD, Bidlingmaier M, Pellegata NS. Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity. Diabetes 2016; 65:406-20. [PMID: 26512025 DOI: 10.2337/db15-0374] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 10/23/2015] [Indexed: 11/13/2022]
Abstract
Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin's proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.
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Affiliation(s)
- Tobias Wiedemann
- Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
| | - Maximilian Bielohuby
- Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
| | - Martin Bidlingmaier
- Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwigs-Maximilians University, Munich, Germany
| | - Natalia S Pellegata
- Institute of Pathology, Helmholtz Center Munich, German Research Center for Environmental Health, Technical University Munich, Munich, Germany
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49
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Jiang FX, Morahan G. Multipotent pancreas progenitors: Inconclusive but pivotal topic. World J Stem Cells 2015; 7:1251-1261. [PMID: 26730269 PMCID: PMC4691693 DOI: 10.4252/wjsc.v7.i11.1251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/20/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023] Open
Abstract
The establishment of multipotent pancreas progenitors (MPP) should have a significant impact not only on the ontology of the pancreas, but also for the translational research of glucose-responding endocrine β-cells. Deficiency of the latter may lead to the pandemic type 1 or type 2 diabetes mellitus, a metabolic disorder. An ideal treatment of which would potentially be the replacement of destroyed or failed β-cells, by restoring function of endogenous pancreatic endocrine cells or by transplantation of donor islets or in vitro generated insulin-secreting cells. Thus, considerable research efforts have been devoted to identify MPP candidates in the pre- and post-natal pancreas for the endogenous neogenesis or regeneration of endocrine insulin-secreting cells. In order to advance this inconclusive but critical field, we here review the emerging concepts, recent literature and newest developments of potential MPP and propose measures that would assist its forward progression.
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50
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King A, Bowe J. Animal models for diabetes: Understanding the pathogenesis and finding new treatments. Biochem Pharmacol 2015; 99:1-10. [PMID: 26432954 DOI: 10.1016/j.bcp.2015.08.108] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/26/2015] [Indexed: 02/06/2023]
Abstract
Diabetes mellitus is a lifelong, metabolic disease that is characterised by an inability to maintain normal glucose homeostasis. There are several different forms of diabetes, however the two most common are Type 1 and Type 2 diabetes. Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells and a subsequent lack of insulin production, whilst Type 2 diabetes is due to a combination of both insulin resistance and an inability of the beta cells to compensate adequately with increased insulin release. Animal models are increasingly being used to elucidate the mechanisms underlying both Type 1 and Type 2 diabetes as well as to identify and refine novel treatments. However, a wide range of different animal models are currently in use. The majority of these models are suited to addressing certain specific aspects of diabetes research, but may be of little use in other studies. All have pros and cons, and selecting an appropriate model for addressing a specific question is not always a trivial task and will influence the study results and their interpretation. Thus, as the number of available animal models increases it is important to consider the potential roles of these models in the many different aspects of diabetes research. This review gathers information on the currently used experimental animal models of both Type 1 and Type 2 diabetes and evaluates their advantages and disadvantages for research purposes and details the factors that should be taken into account in their use.
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Affiliation(s)
- Aileen King
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Hodgkin Building 2nd Floor, Guy's Campus, King's College London, London SE1 1UL, United Kingdom.
| | - James Bowe
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, Hodgkin Building 2nd Floor, Guy's Campus, King's College London, London SE1 1UL, United Kingdom
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