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Kwon Y, Yoon H, Ha J, Lee HS, Pahk K, Kwon H, Kim S, Park S. Changes in pancreatic levodopa uptake in patients with obesity and new-onset type 2 diabetes: an 18F-FDOPA PET-CT study. Front Endocrinol (Lausanne) 2025; 16:1460253. [PMID: 40099262 PMCID: PMC11911206 DOI: 10.3389/fendo.2025.1460253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 01/23/2025] [Indexed: 03/19/2025] Open
Abstract
Introduction Levodopa (L-3,4-dihydroxyphenylalanine)g, a dopamine precursor that circulates in the peripheral region, is involved in pancreatic glycemic control. Although previous animal studies have shown that peripheral levodopa is correlated with insulin secretion in pancreatic beta cells, the mechanism by which the pancreas uses levodopa differently in humans with obesity and type 2 diabetes remains unknown. Our study aimed to observe how the pancreas uptakes and utilizes levodopa differently under obese and diabetic conditions. Materials and method 18F-fluoro-L-dopa positron emission tomography-computed tomography (18F-FDOPA PET-CT) was used to visualize how the human body uses levodopa under obese and diabetic conditions and presented its clinical implications. 10 patients were divided into 3 groups: 1) Group A, normal weight without type 2 diabetes; 2) Group B, obese without type 2 diabetes; and 3) Group C, obese with new-onset type 2 diabetes. All patients' lifestyle modification was conducted prior to 18F-FDOPA PET-CT, and plasma samples were collected to confirm changes in amino acid metabolites. Results Pancreatic levodopa uptake increased in obese patients with insulin resistance, whereas it decreased in obese patients with new-onset type 2 diabetes [standardized uptake value (SUV) mean in participants with normal weight, 2.6 ± 0.7; SUVmean in patients with obesity, 3.6 ± 0.1; SUVmean in patients with obesity and new-onset type 2 diabetes, 2.6 ± 0.1, P = 0.02]. Conclusions This suggested that the alterations in the functional capacity of pancreatic beta cells to take up circulating levodopa are potentially linked to the insulin resistance and the pathogenesis of type 2 diabetes. The differences in the uptake values between the groups implied that pancreatic levodopa uptake could be an early indicator of type 2 diabetes.
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Affiliation(s)
- Yeongkeun Kwon
- Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, Republic of Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, Republic of Korea
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hanseok Yoon
- Division of Biotechnology, Korea University, Seoul, Republic of Korea
| | - Jane Ha
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, United States
| | - Hyeon-seong Lee
- Gangneung Institute of Natural Products, Korea Institute of Science and Technology, Gangneung, Republic of Korea
| | - Kisoo Pahk
- Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Hyunwoo Kwon
- Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sungeun Kim
- Department of Nuclear Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sungsoo Park
- Center for Obesity and Metabolic Diseases, Korea University Anam Hospital, Seoul, Republic of Korea
- Gut & Metabolism Laboratory, Korea University College of Medicine, Seoul, Republic of Korea
- Division of Foregut Surgery, Korea University College of Medicine, Seoul, Republic of Korea
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Galinelli NC, Bamford NJ, Erdody ML, Warnken T, de Laat MA, Sillence MN, Harris PA, Bailey SR. Effect of short-term dopamine reduction on insulin sensitivity and post-prandial insulin and glucose responses in Standardbred horses. Domest Anim Endocrinol 2025; 90:106893. [PMID: 39486097 DOI: 10.1016/j.domaniend.2024.106893] [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: 07/02/2024] [Revised: 09/30/2024] [Accepted: 10/18/2024] [Indexed: 11/04/2024]
Abstract
The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses.
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Affiliation(s)
- Nicolas C Galinelli
- Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Nicholas J Bamford
- Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Madison L Erdody
- Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia
| | - Tobias Warnken
- Boehringer Ingelheim Vetmedica GmbH, Ingelheim am Rhein, Germany
| | - Melody A de Laat
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Martin N Sillence
- School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Patricia A Harris
- Equine Studies Group, Waltham Petcare Science Institute, Melton Mowbray, United Kingdom
| | - Simon R Bailey
- Melbourne Veterinary School, The University of Melbourne, Parkville, Victoria, Australia.
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Mthana MS, Mthiyane DMN. High dietary Mucuna pruriens utilis seed meal compromises growth performance, carcass traits, haemato-biochemistry, and meat quality of broilers. Trop Anim Health Prod 2024; 56:310. [PMID: 39352513 PMCID: PMC11445329 DOI: 10.1007/s11250-024-04120-w] [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: 05/04/2024] [Accepted: 09/11/2024] [Indexed: 10/04/2024]
Abstract
Usage of soyabean meal (SBM) in broiler diets is economically and environmentally unsustainable thus necessitating investigation of alternative protein sources. Therefore, this study investigated effects of incremental inclusion levels of Mucuna pruriens utilis seed meal (MSM) for partial substitution of SBM in broiler diets. In a completely randomized design (CRD), 400 day-old Ross 308 chicks were allotted to 5 iso-caloric-nitrogenous MSM-containing (0, 5, 10, 15, and 20%) dietary treatments. Each treatment was replicated 8 times, with each pen having 10 birds, during starter (d1 - 14), grower (d15 - 28), and finisher (d29 - 42) phases. Results showed that dietary MSM decreased feed intake (FI: quadratic: P < 0.001), body weight gain (BWG: linear: P < 0.001), and feed conversion efficiency (FCE: linear: P < 0.001) as it linearly decreased slaughter weight (SW: P < 0.001), hot carcass weight (HCW: P < 0.001), cold carcass weight (CCW: P < 0.001), dressing percentage (P < 0.001), and breast weight (P < 0.05). In contrast, dietary MSM linearly increased the weights of the liver (P < 0.01), proventriculus (P < 0.001), gizzard (P < 0.001), duodenum (P = 0.01), jejunum (P < 0.001), ileum (P < 0.001), caecum (P < 0.01), and colon (P < 0.01). Also, dietary MSM quadratically increased blood heterophils (P < 0.05) and alkaline phosphatase activity (P < 0.05) of the chickens whilst linearly increasing their serum amylase (P = 0.001) and lipase (P = 0.001) activities and linearly decreasing their serum symmetric dimethylarginine (SDMA: P = 0.001) and cholesterol (P < 0.05). Further, dietary MSM linearly decreased chicken breast meat ultimate pH (P < 0.05) whilst linearly increasing its cooking loss (P < 0.01), drip loss (P < 0.05) and shear force (P < 0.01). In conclusion, dietary MSM compromised growth performance, carcass characteristics, and meat quality of broilers as it increased the weights of their digestive-metabolic organs.
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Affiliation(s)
- Makiwa Simeon Mthana
- Department of Animal Science, School of Agricultural Sciences, Faculty of Natural and Agricultural Sciences, North-West University (Mahikeng Campus), Private Bag X 2046, Mmabatho, 2735, South Africa
| | - Doctor Mziwenkosi Nhlanhla Mthiyane
- Department of Animal Science, School of Agricultural Sciences, Faculty of Natural and Agricultural Sciences, North-West University (Mahikeng Campus), Private Bag X 2046, Mmabatho, 2735, South Africa.
- Food Security and Safety Focus Area, Faculty of Natural and Agricultural Sciences, North-West University (Mahikeng Campus), Mmabatho, 2735, South Africa.
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Komici K, Pansini A, Bencivenga L, Rengo G, Pagano G, Guerra G. Frailty and Parkinson's disease: the role of diabetes mellitus. Front Med (Lausanne) 2024; 11:1377975. [PMID: 38882667 PMCID: PMC11177766 DOI: 10.3389/fmed.2024.1377975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/02/2024] [Indexed: 06/18/2024] Open
Abstract
Parkinson's disease (PD) is a chronic neurodegenerative disease associated with a progressive loss of dopaminergic neurons, clinically characterized by motor and non-motor signs. Frailty is a clinical condition of increased vulnerability and negative health outcomes due to the loss of multiple physiological reserves. Chronic hyperglycemia and insulin resistance, which characterize diabetes mellitus (DM), have been reported to alter dopaminergic activity, increase the risk of PD, and influence the development of frailty. Even though diabetes may facilitate the development of frailty in patients with PD, this relationship is not established and a revision of the current knowledge is necessary. Furthermore, the synergy between DM, PD, and frailty may drive clinical complexity, worse outcomes, and under-representation of these populations in the research. In this review, we aimed to discuss the role of diabetes in the development of frailty among patients with PD. We summarized the clinical characteristics and outcomes of patients with concomitant DM, PD, and frailty. Finally, interventions to prevent frailty in this population are discussed.
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Affiliation(s)
- Klara Komici
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | | | - Leonardo Bencivenga
- Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
| | - Giuseppe Rengo
- Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy
- Istituti Clinici Scientifici Maugeri IRCCS-Scientific Institute of Telese Terme, Telese Terme, BN, Italy
| | - Gennaro Pagano
- Roche Pharma Research and Early Development (pRED), Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center, Basel, Switzerland
- University of Exeter Medical School, London, United Kingdom
| | - Germano Guerra
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
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Lisco G, De Tullio A, Iovino M, Disoteo O, Guastamacchia E, Giagulli VA, Triggiani V. Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes. Biomedicines 2023; 11:2993. [PMID: 38001993 PMCID: PMC10669051 DOI: 10.3390/biomedicines11112993] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson's and Huntington's diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.
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Affiliation(s)
- Giuseppe Lisco
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
| | - Anna De Tullio
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
| | - Michele Iovino
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
| | - Olga Disoteo
- Diabetology Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy;
| | - Edoardo Guastamacchia
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
| | - Vito Angelo Giagulli
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
| | - Vincenzo Triggiani
- Interdisciplinary Department of Medicine, School of Medicine, University of Bari, 70124 Bari, Italy; (G.L.); (A.D.T.); (M.I.); (E.G.); (V.A.G.)
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Rachdi L, Zhou Z, Berthault C, Lourenço C, Fouque A, Domet T, Armanet M, You S, Peakman M, Mallone R, Scharfmann R. Tryptophan metabolism promotes immune evasion in human pancreatic β cells. EBioMedicine 2023; 95:104740. [PMID: 37536063 PMCID: PMC10412781 DOI: 10.1016/j.ebiom.2023.104740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 08/05/2023] Open
Abstract
BACKGROUND To resist the autoimmune attack characteristic of type 1 diabetes, insulin producing pancreatic β cells need to evade T-cell recognition. Such escape mechanisms may be conferred by low HLA class I (HLA-I) expression and upregulation of immune inhibitory molecules such as Programmed cell Death Ligand 1 (PD-L1). METHODS The expression of PD-L1, HLA-I and CXCL10 was evaluated in the human β cell line, ECN90, and in primary human and mouse pancreatic islets. Most genes were determined by real-time RT-PCR, flow cytometry and Western blot. Activator and inhibitor of the AKT signaling were used to modulate PD-L1 induction. Key results were validated by monitoring activity of CD8+ Jurkat T cells presenting β cell specific T-cell receptor and transduced with reporter genes in contact culture with the human β cell line, ECN90. FINDINGS In this study, we identify tryptophan (TRP) as an agonist of PD-L1 induction through the AKT signaling pathway. TRP also synergistically enhanced PD-L1 expression on β cells exposed to interferon-γ. Conversely, interferon-γ-mediated induction of HLA-I and CXCL10 genes was down-regulated upon TRP treatment. Finally, TRP and its derivatives inhibited the activation of islet-reactive CD8+ T cells by β cells. INTERPRETATION Collectively, our findings indicate that TRP could induce immune tolerance to β cells by promoting their immune evasion through HLA-I downregulation and PD-L1 upregulation. FUNDING Dutch Diabetes Research Foundation, DON Foundation, the Laboratoire d'Excellence consortium Revive (ANR-10-LABX-0073), Agence Nationale de la Recherche (ANR-19-CE15-0014-01), Fondation pour la Recherche Médicale (EQ U201903007793-EQU20193007831), Innovative Medicines InitiativeINNODIA and INNODIA HARVEST, Aides aux Jeunes Diabetiques (AJD) and Juvenile Diabetes Research Foundation Ltd (JDRF).
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Affiliation(s)
- Latif Rachdi
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France.
| | - Zhicheng Zhou
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
| | - Claire Berthault
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
| | - Chloe Lourenço
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
| | - Alexis Fouque
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
| | - Thomas Domet
- Assistance Publique Hôpitaux de Paris, Cell Therapy Unit, Saint Louis Hospital, Paris 75010, France
| | - Mathieu Armanet
- Assistance Publique Hôpitaux de Paris, Cell Therapy Unit, Saint Louis Hospital, Paris 75010, France
| | - Sylvaine You
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
| | - Mark Peakman
- Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London SE1 9RT, UK
| | - Roberto Mallone
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France; Assistance Publique Hôpitaux de Paris, Service de Diabétologie et Immunologie Clinique, Cochin Hospital, Paris 75014, France
| | - Raphael Scharfmann
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris 75014, France
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Freyberg Z, Gittes GK. Roles of Pancreatic Islet Catecholamine Neurotransmitters in Glycemic Control and in Antipsychotic Drug-Induced Dysglycemia. Diabetes 2023; 72:3-15. [PMID: 36538602 PMCID: PMC9797319 DOI: 10.2337/db22-0522] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 09/24/2022] [Indexed: 12/24/2022]
Abstract
Catecholamine neurotransmitters dopamine (DA) and norepinephrine (NE) are essential for a myriad of functions throughout the central nervous system, including metabolic regulation. These molecules are also present in the pancreas, and their study may shed light on the effects of peripheral neurotransmission on glycemic control. Though sympathetic innervation to islets provides NE that signals at local α-cell and β-cell adrenergic receptors to modify hormone secretion, α-cells and β-cells also synthesize catecholamines locally. We propose a model where α-cells and β-cells take up catecholamine precursors in response to postprandial availability, preferentially synthesizing DA. The newly synthesized DA signals in an autocrine/paracrine manner to regulate insulin and glucagon secretion and maintain glycemic control. This enables islets to couple local catecholamine signaling to changes in nutritional state. We also contend that the DA receptors expressed by α-cells and β-cells are targeted by antipsychotic drugs (APDs)-some of the most widely prescribed medications today. Blockade of local DA signaling contributes significantly to APD-induced dysglycemia, a major contributor to treatment discontinuation and development of diabetes. Thus, elucidating the peripheral actions of catecholamines will provide new insights into the regulation of metabolic pathways and may lead to novel, more effective strategies to tune metabolism and treat diabetes.
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Affiliation(s)
- Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA
| | - George K. Gittes
- Division of Pediatric Surgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA
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Asai S, Moravcová J, Žáková L, Selicharová I, Hadravová R, Brzozowski AM, Nováček J, Jiráček J. Characterization of insulin crystalline form in isolated β-cell secretory granules. Open Biol 2022; 12:220322. [PMID: 36541100 PMCID: PMC9768635 DOI: 10.1098/rsob.220322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Insulin is stored in vivo inside the pancreatic β-cell insulin secretory granules. In vitro studies have led to an assumption that high insulin and Zn2+ concentrations inside the pancreatic β-cell insulin secretory granules should promote insulin crystalline state in the form of Zn2+-stabilized hexamers. Electron microscopic images of thin sections of the pancreatic β-cells often show a dense, regular pattern core, suggesting the presence of insulin crystals. However, the structural features of the storage forms of insulin in native preparations of secretory granules are unknown, because of their small size, fragile character and difficult handling. We isolated and investigated the secretory granules from MIN6 cells under near-native conditions, using cryo-electron microscopic (Cryo-EM) techniques. The analysis of these data from multiple intra-granular crystals revealed two different rhomboidal crystal lattices. The minor lattice has unit cell parameters (a ≃ b ≃ 84.0 Å, c ≃ 35.2 Å), similar to in vitro crystallized human 4Zn2+-insulin hexamer, whereas the largely prevalent unit cell has more than double c-axis (a ≃ b ≃ c ≃ 96.5 Å) that probably corresponds to two or three insulin hexamers in the asymmetric unit. Our experimental data show that insulin can be present in pancreatic MIN6 cell granules in a microcrystalline form, probably consisting of 4Zn2+-hexamers of this hormone.
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Affiliation(s)
- Seiya Asai
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 11610 Prague 6, Czech Republic,Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic
| | - Jana Moravcová
- CEITEC, Cryo-Electron Microscopy and Tomography Core Facility, Masaryk University, Kamenice 5, 62500 Bohunice, Czech Republic
| | - Lenka Žáková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 11610 Prague 6, Czech Republic
| | - Irena Selicharová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 11610 Prague 6, Czech Republic
| | - Romana Hadravová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 11610 Prague 6, Czech Republic
| | - Andrzej Marek Brzozowski
- York Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
| | - Jiří Nováček
- CEITEC, Cryo-Electron Microscopy and Tomography Core Facility, Masaryk University, Kamenice 5, 62500 Bohunice, Czech Republic
| | - Jiří Jiráček
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 11610 Prague 6, Czech Republic
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De Iuliis A, Montinaro E, Fatati G, Plebani M, Colosimo C. Diabetes mellitus and Parkinson's disease: dangerous liaisons between insulin and dopamine. Neural Regen Res 2022; 17:523-533. [PMID: 34380882 PMCID: PMC8504381 DOI: 10.4103/1673-5374.320965] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 02/08/2021] [Accepted: 03/04/2021] [Indexed: 11/13/2022] Open
Abstract
The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960s to date. Molecular studies have shown the possible functional link between insulin and dopamine, as there is strong evidence demonstrating the action of dopamine in pancreatic islets, as well as the insulin effects on feeding and cognition through central nervous system mechanism, largely independent of glucose utilization. Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease, while an old dopamine agonist, bromocriptine, has been repositioned for the type 2 diabetes mellitus treatment. This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease.
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Affiliation(s)
| | - Ennio Montinaro
- Department of Neurology, Santa Maria University Hospital, Terni, Italy
| | | | - Mario Plebani
- Department of Medicine-DiMED, University of Padova, Italy
- Department of Medicine-DiMED, University of Padova, Padova, Italy; Department of Laboratory Medicine-Hospital of Padova, Padova, Italy
| | - Carlo Colosimo
- Department of Neurology, Santa Maria University Hospital, Terni, Italy
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10
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Pirchio R, Graziadio C, Colao A, Pivonello R, Auriemma RS. Metabolic effects of prolactin. Front Endocrinol (Lausanne) 2022; 13:1015520. [PMID: 36237192 PMCID: PMC9552666 DOI: 10.3389/fendo.2022.1015520] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/05/2022] [Indexed: 11/23/2022] Open
Abstract
Over the last years, the metabolic role of PRL has emerged. PRL excess is known to promote weight gain, obesity, metabolic syndrome, and impairment in gluco-insulinemic and lipid profiles, likely due to the suppression of physiologic dopaminergic tone. Prolactin receptors and dopamine receptors type 2 have been demonstrated to be expressed on both human pancreatic β- cell and adipocytes, supporting a key role of prolactin and dopamine in peripheral metabolic regulation. Medical treatment with the dopamine agonists bromocriptine and cabergoline has been demonstrated to decrease the prevalence of metabolic syndrome and obesity, and significantly improve gluco-insulinemic and lipid profiles. In hyperprolactinemic men with concomitant hypogonadism, correction of hyperprolactinaemia and testosterone replacement has been proven to restore metabolic impairment. In turn, low prolactin levels have also been demonstrated to exert a detrimental effect on weight gain, glucose and lipid metabolism, thus leading to an increased prevalence of metabolic syndrome. Therefore, PRL values ranging from 25 to 100 mg/L, in absence of other recognizable pathological causes, have been proposed to represent a physiological response to the request for an increase in metabolic activity, and nowadays classify the so-called HomeoFIT- PRL as a promoter of metabolic homeostasis. The current review focuses mainly on the effects of hyperprolactinemia and its control by medical treatment with DAs on the modulation of food intake, body weight, gluco-insulinemic and lipid profile. Furthermore, it provides the latest knowledge about the metabolic impact of hypoprolactinemia.
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Affiliation(s)
- Rosa Pirchio
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University of Naples Federico II, Naples, Italy
| | - Chiara Graziadio
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University of Naples Federico II, Naples, Italy
| | - Annamaria Colao
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University of Naples Federico II, Naples, Italy
- Unesco Chair for Health Education and Sustainable Development, “Federico II” University, Naples, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University of Naples Federico II, Naples, Italy
- Unesco Chair for Health Education and Sustainable Development, “Federico II” University, Naples, Italy
| | - Renata S. Auriemma
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, University of Naples Federico II, Naples, Italy
- *Correspondence: Renata S. Auriemma,
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11
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Germanos M, Gao A, Taper M, Yau B, Kebede MA. Inside the Insulin Secretory Granule. Metabolites 2021; 11:metabo11080515. [PMID: 34436456 PMCID: PMC8401130 DOI: 10.3390/metabo11080515] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 12/19/2022] Open
Abstract
The pancreatic β-cell is purpose-built for the production and secretion of insulin, the only hormone that can remove glucose from the bloodstream. Insulin is kept inside miniature membrane-bound storage compartments known as secretory granules (SGs), and these specialized organelles can readily fuse with the plasma membrane upon cellular stimulation to release insulin. Insulin is synthesized in the endoplasmic reticulum (ER) as a biologically inactive precursor, proinsulin, along with several other proteins that will also become members of the insulin SG. Their coordinated synthesis enables synchronized transit through the ER and Golgi apparatus for congregation at the trans-Golgi network, the initiating site of SG biogenesis. Here, proinsulin and its constituents enter the SG where conditions are optimized for proinsulin processing into insulin and subsequent insulin storage. A healthy β-cell is continually generating SGs to supply insulin in vast excess to what is secreted. Conversely, in type 2 diabetes (T2D), the inability of failing β-cells to secrete may be due to the limited biosynthesis of new insulin. Factors that drive the formation and maturation of SGs and thus the production of insulin are therefore critical for systemic glucose control. Here, we detail the formative hours of the insulin SG from the luminal perspective. We do this by mapping the journey of individual members of the SG as they contribute to its genesis.
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12
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Asai S, Žáková L, Selicharová I, Marek A, Jiráček J. A radioligand receptor binding assay for measuring of insulin secreted by MIN6 cells after stimulation with glucose, arginine, ornithine, dopamine, and serotonin. Anal Bioanal Chem 2021; 413:4531-4543. [PMID: 34050775 DOI: 10.1007/s00216-021-03423-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/07/2021] [Accepted: 05/20/2021] [Indexed: 12/31/2022]
Abstract
We adapted a radioligand receptor binding assay for measuring insulin levels in unknown samples. The assay enables rapid and accurate determination of insulin concentrations in experimental samples, such as from insulin-secreting cells. The principle of the method is based on the binding competition of insulin in a measured sample with a radiolabeled insulin for insulin receptor (IR) in IM-9 cells. Both key components, radiolabeled insulin and IM-9 cells, are commercially available. The IR binding assay was used to determine unknown amounts of insulin secreted by MIN6 β cell line after stimulation with glucose, arginine, ornithine, dopamine, and serotonin. The experimental data obtained by the IR binding assay were compared to the results determined by RIA kits and both methods showed a very good agreement of results. We observed the stimulation of glucose-induced insulin secretion from MIN6 cells by arginine, weaker stimulation by ornithine, but inhibitory effects of dopamine. Serotonin effects were either stimulatory or inhibitory, depending on the concentration of serotonin used. The results will require further investigation. The study also clearly revealed advantages of the IR binding assay that allows the measuring of a higher throughput of measured samples, with a broader range of concentrations than in the case of RIA kits. The IR binding assay can provide an alternative to standard RIA and ELISA assays for the determination of insulin levels in experimental samples and can be especially useful in scientific laboratories studying insulin production and secretion by β cells and searching for new modulators of insulin secretion.
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Affiliation(s)
- Seiya Asai
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
- Department of Biochemistry, Faculty of Science, Charles University, 12840, Prague 2, Czech Republic
| | - Lenka Žáková
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Irena Selicharová
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Aleš Marek
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic
| | - Jiří Jiráček
- Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nám. 2, 116 10, Prague 6, Czech Republic.
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13
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Aslanoglou D, Bertera S, Sánchez-Soto M, Benjamin Free R, Lee J, Zong W, Xue X, Shrestha S, Brissova M, Logan RW, Wollheim CB, Trucco M, Yechoor VK, Sibley DR, Bottino R, Freyberg Z. Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors. Transl Psychiatry 2021; 11:59. [PMID: 33589583 PMCID: PMC7884786 DOI: 10.1038/s41398-020-01171-z] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/13/2020] [Accepted: 10/26/2020] [Indexed: 01/14/2023] Open
Abstract
Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α2A-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D2-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
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Affiliation(s)
- Despoina Aslanoglou
- grid.21925.3d0000 0004 1936 9000Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA
| | - Suzanne Bertera
- grid.417046.00000 0004 0454 5075Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA USA
| | - Marta Sánchez-Soto
- grid.94365.3d0000 0001 2297 5165Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD USA
| | - R. Benjamin Free
- grid.94365.3d0000 0001 2297 5165Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD USA
| | - Jeongkyung Lee
- grid.21925.3d0000 0004 1936 9000Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Diabetes and Beta Cell Biology Center, University of Pittsburgh, Pittsburgh, PA USA
| | - Wei Zong
- grid.21925.3d0000 0004 1936 9000Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA USA
| | - Xiangning Xue
- grid.21925.3d0000 0004 1936 9000Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA USA
| | - Shristi Shrestha
- grid.412807.80000 0004 1936 9916Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA
| | - Marcela Brissova
- grid.412807.80000 0004 1936 9916Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA
| | - Ryan W. Logan
- grid.21925.3d0000 0004 1936 9000Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA USA ,grid.249880.f0000 0004 0374 0039Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME USA
| | - Claes B. Wollheim
- grid.8591.50000 0001 2322 4988Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland
| | - Massimo Trucco
- grid.417046.00000 0004 0454 5075Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA USA ,grid.147455.60000 0001 2097 0344Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA USA ,grid.166341.70000 0001 2181 3113College of Medicine, Drexel University, Philadelphia, PA USA
| | - Vijay K. Yechoor
- grid.21925.3d0000 0004 1936 9000Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Diabetes and Beta Cell Biology Center, University of Pittsburgh, Pittsburgh, PA USA
| | - David R. Sibley
- grid.94365.3d0000 0001 2297 5165Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD USA
| | - Rita Bottino
- grid.417046.00000 0004 0454 5075Institute of Cellular Therapeutics, Allegheny Health Network Research Institute, Allegheny Health Network, Pittsburgh, PA USA ,grid.147455.60000 0001 2097 0344Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA USA ,grid.166341.70000 0001 2181 3113College of Medicine, Drexel University, Philadelphia, PA USA
| | - Zachary Freyberg
- Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. .,Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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14
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Mitrofanova LB, Perminova AA, Ryzhkova DV, Sukhotskaya AA, Bairov VG, Nikitina IL. Differential Morphological Diagnosis of Various Forms of Congenital Hyperinsulinism in Children. Front Endocrinol (Lausanne) 2021; 12:710947. [PMID: 34497584 PMCID: PMC8419459 DOI: 10.3389/fendo.2021.710947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/04/2021] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Congenital hyperinsulinism (CHI) has diffuse (CHI-D), focal (CHI-F) and atypical (CHI-A) forms. Surgical management depends on preoperative [18F]-DOPA PET/CT and intraoperative morphological differential diagnosis of CHI forms. Objective: to improve differential diagnosis of CHI forms by comparative analysis [18F]-DOPA PET/CT data, as well as cytological, histological and immunohistochemical analysis (CHIA). MATERIALS AND METHODS The study included 35 CHI patients aged 3.2 ± 2.0 months; 10 patients who died from congenital heart disease at the age of 3.2 ± 2.9 months (control group). We used PET/CT, CHIA of pancreas with antibodies to ChrA, insulin, Isl1, Nkx2.2, SST, NeuroD1, SSTR2, SSTR5, DR1, DR2, DR5; fluorescence microscopy with NeuroD1/ChrA, Isl1/insulin, insulin/SSTR2, DR2/NeuroD1 cocktails. RESULTS Intraoperative examination of pancreatic smears showed the presence of large nuclei, on average, in: 14.5 ± 3.5 cells of CHI-F; 8.4 ± 1.1 of CHI-D; and 4.5 ± 0.7 of control group (from 10 fields of view, x400). The percentage of Isl1+ and NeuroD1+endocrinocytes significantly differed from that in the control for all forms of CHI. The percentage of NeuroD1+exocrinocytes was also significantly higher than in the control. The proportion of ChrA+ and DR2+endocrinocytes was higher in CHI-D than in CHI-F, while the proportion of insulin+cells was higher in CHI-A. The number of SST+cells was significantly higher in CHI-D and CHI-F than in CHI-A. CONCLUSION For intraoperative differential diagnosis of CHI forms, in addition to frozen sections, quantitative cytological analysis can be used. In quantitative immunohistochemistry, CHI forms differ in the expression of ChrA, insulin, SST and DR2. The development of a NeuroD1 inhibitor would be advisable for targeted therapy of CHI.
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15
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Farino ZJ, Morgenstern TJ, Maffei A, Quick M, De Solis AJ, Wiriyasermkul P, Freyberg RJ, Aslanoglou D, Sorisio D, Inbar BP, Free RB, Donthamsetti P, Mosharov EV, Kellendonk C, Schwartz GJ, Sibley DR, Schmauss C, Zeltser LM, Moore H, Harris PE, Javitch JA, Freyberg Z. New roles for dopamine D 2 and D 3 receptors in pancreatic beta cell insulin secretion. Mol Psychiatry 2020; 25:2070-2085. [PMID: 30626912 PMCID: PMC6616020 DOI: 10.1038/s41380-018-0344-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 09/17/2018] [Accepted: 12/10/2018] [Indexed: 01/11/2023]
Abstract
Although long-studied in the central nervous system, there is increasing evidence that dopamine (DA) has important roles in the periphery including in metabolic regulation. Insulin-secreting pancreatic β-cells express the machinery for DA synthesis and catabolism, as well as all five DA receptors. In these cells, DA functions as a negative regulator of glucose-stimulated insulin secretion (GSIS), which is mediated by DA D2-like receptors including D2 (D2R) and D3 (D3R) receptors. However, the fundamental mechanisms of DA synthesis, storage, release, and signaling in pancreatic β-cells and their functional relevance in vivo remain poorly understood. Here, we assessed the roles of the DA precursor L-DOPA in β-cell DA synthesis and release in conjunction with the signaling mechanisms underlying DA's inhibition of GSIS. Our results show that the uptake of L-DOPA is essential for establishing intracellular DA stores in β-cells. Glucose stimulation significantly enhances L-DOPA uptake, leading to increased DA release and GSIS reduction in an autocrine/paracrine manner. Furthermore, D2R and D3R act in combination to mediate dopaminergic inhibition of GSIS. Transgenic knockout mice in which β-cell D2R or D3R expression is eliminated exhibit diminished DA secretion during glucose stimulation, suggesting a new mechanism where D2-like receptors modify DA release to modulate GSIS. Lastly, β-cell-selective D2R knockout mice exhibit marked postprandial hyperinsulinemia in vivo. These results reveal that peripheral D2R and D3R receptors play important roles in metabolism through their inhibitory effects on GSIS. This opens the possibility that blockade of peripheral D2-like receptors by drugs including antipsychotic medications may significantly contribute to the metabolic disturbances observed clinically.
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Affiliation(s)
- Zachary J. Farino
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Travis J. Morgenstern
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Antonella Maffei
- Division of Endocrinology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Matthias Quick
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Alain J. De Solis
- Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
| | - Pattama Wiriyasermkul
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Current address: Department of Collaborative Research, Nara Medical University, Kashihara, Nara, Japan
| | - Robin J. Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Denise Sorisio
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Benjamin P. Inbar
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - R. Benjamin Free
- Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Prashant Donthamsetti
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Current address: Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
| | - Eugene V. Mosharov
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA,Department of Neurology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Christoph Kellendonk
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA,Department of Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Gary J. Schwartz
- Departments of Medicine and Neuroscience, Albert Einstein College of Medicine, Bronx, NY, USA
| | - David R. Sibley
- Molecular Neuropharmacology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Claudia Schmauss
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA
| | - Lori M. Zeltser
- Division of Molecular Genetics, Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA,Department of Pathology and Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Holly Moore
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA
| | - Paul E. Harris
- Division of Endocrinology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Jonathan A. Javitch
- Department of Psychiatry, College of Physicians & Surgeons, Columbia University, New York, NY, USA,Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA,Department of Pharmacology, College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA. .,Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA.
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16
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Analysis of the Relationship between Type II Diabetes Mellitus and Parkinson's Disease: A Systematic Review. PARKINSONS DISEASE 2019; 2019:4951379. [PMID: 31871617 PMCID: PMC6906831 DOI: 10.1155/2019/4951379] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 10/01/2019] [Accepted: 11/06/2019] [Indexed: 12/31/2022]
Abstract
In the early sixties, a discussion started regarding the association between Parkinson's disease (PD) and type II diabetes mellitus (T2DM). Today, this potential relationship is still a matter of debate. This review aims to analyze both diseases concerning causal relationships and treatments. A total of 104 articles were found, and studies on animal and “in vitro” models showed that T2DM causes neurological alterations that may be associated with PD, such as deregulation of the dopaminergic system, a decrease in the expression of peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), an increase in the expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes 15 (PED/PEA-15), and neuroinflammation, as well as acceleration of the formation of alpha-synuclein amyloid fibrils. In addition, clinical studies described that Parkinson's symptoms were notably worse after the onset of T2DM, and seven deregulated genes were identified in the DNA of T2DM and PD patients. Regarding treatment, the action of antidiabetic drugs, especially incretin mimetic agents, seems to confer certain degree of neuroprotection to PD patients. In conclusion, the available evidence on the interaction between T2DM and PD justifies more robust clinical trials exploring this interaction especially the clinical management of patients with both conditions.
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17
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Korner J, Cline GW, Slifstein M, Barba P, Rayat GR, Febres G, Leibel RL, Maffei A, Harris PE. A role for foregut tyrosine metabolism in glucose tolerance. Mol Metab 2019; 23:37-50. [PMID: 30876866 PMCID: PMC6479665 DOI: 10.1016/j.molmet.2019.02.008] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 02/14/2019] [Accepted: 02/24/2019] [Indexed: 01/13/2023] Open
Abstract
Objective We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. Methods To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients. Next, we characterized: 1) the metabolic transformation of TYR and L-DOPA into DA in vitro using purified islet tissue; 2) the metabolic transformation of orally administrated stable isotope labeled TYR into pancreatic DA, and 3) using a nuclear medicine technique, we studied endocrine beta cells in situ release and binding of DA in response to a glucose challenge. Results We demonstrate in rodents that intestinal content and circulatory concentrations L-DOPA and DA, plasma glucose and insulin are responsive to the tyrosine (TYR) content of a test meal. Intestinal expression of two enzymes, Tyrosine hydroxylase (TH) and Aromatic Amino acid Decarboxylase (AADC), essential to the transformation of TYR to DA was mapped and the metabolism of metabolism of TYR to DA was traced in human islets and a rodent beta cell line in vitro and from gut to the pancreas in vivo. Lastly, we show that β cells secrete and bind DA in situ in response to glucose stimulation. Conclusions We provide proof-of-principle evidence for the existence of a novel postprandial circuit of glucose homeostasis dependent on nutritional tyrosine. DA and L-DOPA derived from nutritional tyrosine may serve to defend against hypoglycemia via inhibition of glucose-stimulated β-cell insulin secretion as proposed by the anti-incretin hypothesis.
Nutritional tyrosine is metabolized to L DOPA and DA in the foregut. Postprandial L-DOPA and DA plasma concentrations rise in response to tyrosine. Oral stable isotope labeled tyrosine is found postprandially in the pancreas as DA. L-DOPA and DA are inhibitors of beta cell glucose-stimulated insulin secretion. Postprandial L-DOPA and DA excursions are muted in certain bariatric surgery patients.
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Affiliation(s)
- Judith Korner
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Gary W Cline
- Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT, 06520, USA
| | - Mark Slifstein
- Department of Psychiatry, Stony Brook University, Stony Brook, New York, NY, 11794, USA
| | - Pasquale Barba
- Institute of Genetics and Biophysics, Adriano Buzzati-Traverso, CNR, Naples, IT 80131, Italy
| | - Gina R Rayat
- Alberta Diabetes Institute, Ray Rajotte Surgical-Medical Research Institute, Department of Surgery, University of Alberta, Edmonton, AB, T6G 2E1 CA, Canada
| | - Gerardo Febres
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Rudolph L Leibel
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Antonella Maffei
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA
| | - Paul E Harris
- Department of Medicine and the Naomi Berrie Diabetes Center, Columbia University, College of Physicians and Surgeons, New York, NY, 10032, USA.
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18
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Auriemma RS, De Alcubierre D, Pirchio R, Pivonello R, Colao A. Glucose Abnormalities Associated to Prolactin Secreting Pituitary Adenomas. Front Endocrinol (Lausanne) 2019; 10:327. [PMID: 31191454 PMCID: PMC6540784 DOI: 10.3389/fendo.2019.00327] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 05/07/2019] [Indexed: 12/15/2022] Open
Abstract
The pathogenesis of obesity and alterations in glucose profile have been linked to PRL excess, as it is reportedly associated with metabolic syndrome in thereabout one third of patients. In vitro exposure of pancreatic islet to PRL is known to stimulate insulin secretion and β-cell proliferation, and in turn overexpression of PRL in β-cells increases insulin release and β-cell replication. PRL excess has been found to worsen glucose profile because it reduces glucose tolerance and induces insulin resistance either in obese and non-obese patients. To note, pancreatic β-cells and adipocytes widely express dopamine receptors type 2, and dopamine has been hypothesized to play a key role as modulator of insulin and adipose functions. The dopamine agonists bromocriptine and cabergoline significantly improve abnormalities in glucose profile and reduce the prevalence of metabolic syndrome in a remarkable proportion of patients, regardless of whether body weight and PRL status may change. However, in men with hyperprolactinemia complicated by hypogonadism, testosterone replacement can ameliorate insulin resistance and abnormalities in glucose metabolism. Therefore, in patients with PRL-secreting pituitary adenomas control of PRL excess by dopamine agonists is mandatory to improve glucose and insulin abnormalities.
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19
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Hassanabad MF, Fatehi M. Current Views on Dopaminergic Drugs Affecting Glucose Homeostasis. Curr Diabetes Rev 2019; 15:93-99. [PMID: 29692257 DOI: 10.2174/1573399814666180424123912] [Citation(s) in RCA: 2] [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: 10/13/2017] [Revised: 04/17/2018] [Accepted: 04/19/2018] [Indexed: 11/22/2022]
Abstract
BACKGROUND For more than three decades, it has been known that manipulation of dopaminergic system could affect glucose homesotasis in experimental animals. The notion that glucose homeostasis in human might be influenced by dopaminergic drugs has attracted a great deal of attention in the past two decades. In spite of rapid advancements in revealing involvement of dopaminergic neurotransmission in insulin release, glucose up-take and pancreatic beta cell function in general through centrally and peripherally controlled mechanisms, there are discrepancies among observations on experimental animals and human subjects. CONCLUSION With the expansion of pharmacotherapy in psychotic conditions, depression and endocrine abnormalities along with a sharp increase in prevalence of type two diabetes and disturbances of glucose homeostasis as a major risk factor for many cardiovascular complications and associated mortalities; it seems a critical analysis of recent investigations on drugs which act as agonists or antagonists of dopaminergic receptors in various tissues and organs may provide better insight into how safe and efficient these medicines could be prescribed. Furthermore, the other main objective of present review is to compare clinical data on significance of changes in blood glucose and insulin levels during short term and after long term treatment with these agents. This in turn would be beneficial for determining adequate strategies to combat or to avoid adverse effects associated with dopaminergic drug therapy.
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Affiliation(s)
- Mortaza Fatehi Hassanabad
- Department of Pharmacology, Alberta Diabetes Institute, Room 6-126 Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, T6G 2E1, Canada
| | - Mohammad Fatehi
- Department of Pharmacology, Alberta Diabetes Institute, Room 6-126 Li Ka Shing Centre for Health Research Innovation, University of Alberta, Edmonton, AB, T6G 2E1, Canada
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Mitok KA, Freiberger EC, Schueler KL, Rabaglia ME, Stapleton DS, Kwiecien NW, Malec PA, Hebert AS, Broman AT, Kennedy RT, Keller MP, Coon JJ, Attie AD. Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion. J Biol Chem 2018; 293:5860-5877. [PMID: 29496998 DOI: 10.1074/jbc.ra117.001102] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/29/2018] [Indexed: 12/11/2022] Open
Abstract
The mouse is a critical model in diabetes research, but most research in mice has been limited to a small number of mouse strains and limited genetic variation. Using the eight founder strains and both sexes of the Collaborative Cross (C57BL/6J (B6), A/J, 129S1/SvImJ (129), NOD/ShiLtJ (NOD), NZO/HILtJ (NZO), PWK/PhJ (PWK), WSB/EiJ (WSB), and CAST/EiJ (CAST)), we investigated the genetic dependence of diabetes-related metabolic phenotypes and insulin secretion. We found that strain background is associated with an extraordinary range in body weight, plasma glucose, insulin, triglycerides, and insulin secretion. Our whole-islet proteomic analysis of the eight mouse strains demonstrates that genetic background exerts a strong influence on the islet proteome that can be linked to the differences in diabetes-related metabolic phenotypes and insulin secretion. We computed protein modules consisting of highly correlated proteins that enrich for biological pathways and provide a searchable database of the islet protein expression profiles. To validate the data resource, we identified tyrosine hydroxylase (Th), a key enzyme in catecholamine synthesis, as a protein that is highly expressed in β-cells of PWK and CAST islets. We show that CAST islets synthesize elevated levels of dopamine, which suppresses insulin secretion. Prior studies, using only the B6 strain, concluded that adult mouse islets do not synthesize l-3,4-dihydroxyphenylalanine (l-DOPA), the product of Th and precursor of dopamine. Thus, the choice of the CAST strain, guided by our islet proteomic survey, was crucial for these discoveries. In summary, we provide a valuable data resource to the research community, and show that proteomic analysis identified a strain-specific pathway by which dopamine synthesized in β-cells inhibits insulin secretion.
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Affiliation(s)
| | | | | | | | | | | | - Paige A Malec
- the Department of Chemistry, University of Michigan-Ann Arbor, Ann Arbor, Michigan 48109
| | - Alexander S Hebert
- the Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, Wisconsin 53706 and
| | | | - Robert T Kennedy
- the Department of Chemistry, University of Michigan-Ann Arbor, Ann Arbor, Michigan 48109
| | | | - Joshua J Coon
- Chemistry, and .,the Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, Wisconsin 53706 and
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Auriemma RS, De Alcubierre D, Pirchio R, Pivonello R, Colao A. The effects of hyperprolactinemia and its control on metabolic diseases. Expert Rev Endocrinol Metab 2018; 13:99-106. [PMID: 30058862 DOI: 10.1080/17446651.2018.1434412] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Hyperprolactinaemia has been implicated in the pathogenesis of obesity and glucose intolerance and is reportedly associated with impaired metabolic profile and metabolic syndrome in approximately one third of patients. AREAS COVERED Suppression of dopaminergic tone has been proposed as a potential mechanism responsible for weight gain and metabolic abnormalities in such patients. Dopamine receptor type 2 (D2R) is abundantly expressed on human pancreatic β-cell and adipocytes, suggesting a regulatory role for peripheral dopamine in insulin and adipose functions. Medical treatment with the dopamine-agonists bromocriptine and cabergoline has been shown to significantly improve gluco-insulinemic and lipid profile, also reducing the prevalence of metabolic syndrome. In patients with concomitant hypogonadism, simultaneous correction of both PRL excess and testosterone deficiency is mandatory to improve insulin resistance and metabolic abnormalities. EXPERT COMMENTARY Hyperprolactinemia promotes metabolic alterations. Control of PRL excess by dopamine agonists is mandatory to induce weight loss and to improve metabolic profile, and replacement treatment for concomitant hypogonadism effectively ameliorates insulin resistance and metabolic syndrome.
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Affiliation(s)
- Renata S Auriemma
- a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia , University of Naples Federico II , Naples , Italy
| | - Dario De Alcubierre
- a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia , University of Naples Federico II , Naples , Italy
| | - Rosa Pirchio
- a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia , University of Naples Federico II , Naples , Italy
| | - Rosario Pivonello
- a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia , University of Naples Federico II , Naples , Italy
| | - Annamaria Colao
- a Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia , University of Naples Federico II , Naples , Italy
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Bini J, Naganawa M, Nabulsi N, Huang Y, Ropchan J, Lim K, Najafzadeh S, Herold KC, Cline GW, Carson RE. Evaluation of PET Brain Radioligands for Imaging Pancreatic β-Cell Mass: Potential Utility of 11C-(+)-PHNO. J Nucl Med 2018; 59:1249-1254. [PMID: 29371405 DOI: 10.2967/jnumed.117.197285] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 12/07/2017] [Indexed: 12/21/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by a loss of β-cells in the islets of Langerhans of the pancreas and subsequent deficient insulin secretion in response to hyperglycemia. Development of an in vivo test to measure β-cell mass (BCM) would greatly enhance the ability to track diabetes therapies. β-cells and neurologic tissues have common cellular receptors and transporters, therefore, we screened brain radioligands for their ability to identify β-cells. Methods: We examined a β-cell gene atlas for endocrine pancreas receptor targets and cross-referenced these targets with brain radioligands that were available at our institution. Twelve healthy control subjects and 2 T1DM subjects underwent dynamic PET/CT scans with 6 tracers. Results: The D2/D3 receptor agonist radioligand 11C-(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) was the only radioligand to demonstrate sustained uptake in the pancreas with high contrast versus abdominal organs such as the kidneys, liver, and spleen, based on the first 30 min of data. Mean SUV from 20 to 30 min demonstrated high uptake of 11C-(+)-PHNO in healthy controls (SUV, 13.8) with a 71% reduction in a T1DM subject with undetectable levels of C-peptide (SUV, 4.0) and a 20% reduction in a T1DM subject with fasting C-peptide level of 0.38 ng/mL (SUV, 11.0). SUV in abdominal organs outside the pancreas did not show measurable differences between the control and T1DM subjects, suggesting that the changes in SUV of 11C-(+)-PHNO may be specific to changes in the pancreas between healthy controls and T1DM subjects. When D3 and D2 antagonists were used in nonhuman primates, specific pancreatic binding (SUVR-1) of 11C-PHNO was reduced by 57% and 38%, respectively. Conclusion:11C-(+)-PHNO is a potential marker of BCM, with 2:1 binding of D3 receptors over D2 receptors. Further in vitro and in vivo studies to establish D2/D3 receptor specificity to β-cells is warranted to characterize 11C-(+)-PHNO as a candidate for clinical measurement of BCM in healthy control and diabetic subjects.
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Affiliation(s)
- Jason Bini
- PET Center, Yale University School of Medicine, New Haven, CT .,Department of Biomedical Engineering, Yale University, New Haven, CT; and
| | - Mika Naganawa
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Nabeel Nabulsi
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Yiyun Huang
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Jim Ropchan
- PET Center, Yale University School of Medicine, New Haven, CT
| | - Keunpoong Lim
- PET Center, Yale University School of Medicine, New Haven, CT
| | | | - Kevan C Herold
- Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Gary W Cline
- Department of Immunobiology and Internal Medicine, Yale University School of Medicine, New Haven, CT
| | - Richard E Carson
- PET Center, Yale University School of Medicine, New Haven, CT.,Department of Biomedical Engineering, Yale University, New Haven, CT; and
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Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacol Res 2016; 109:74-80. [DOI: 10.1016/j.phrs.2015.12.029] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 12/22/2015] [Accepted: 12/22/2015] [Indexed: 01/01/2023]
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Garcia Barrado MJ, Iglesias Osma MC, Blanco EJ, Carretero Hernández M, Sánchez Robledo V, Catalano Iniesta L, Carrero S, Carretero J. Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells. PLoS One 2015; 10:e0123197. [PMID: 25886074 PMCID: PMC4401745 DOI: 10.1371/journal.pone.0123197] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 02/18/2015] [Indexed: 12/30/2022] Open
Abstract
The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen), and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01), by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01) after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01) following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets.
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Affiliation(s)
- Maria Jose Garcia Barrado
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
- Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León, and Laboratory of Neuroendocrinology and Obesity of IBSAL, University of Salamanca, Salamanca, Spain
| | - Maria Carmen Iglesias Osma
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
- Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León, and Laboratory of Neuroendocrinology and Obesity of IBSAL, University of Salamanca, Salamanca, Spain
| | - Enrique J. Blanco
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
- Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León, and Laboratory of Neuroendocrinology and Obesity of IBSAL, University of Salamanca, Salamanca, Spain
| | - Marta Carretero Hernández
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
| | - Virginia Sánchez Robledo
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
| | - Leonardo Catalano Iniesta
- Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
| | - Sixto Carrero
- Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León, and Laboratory of Neuroendocrinology and Obesity of IBSAL, University of Salamanca, Salamanca, Spain
| | - Jose Carretero
- Department of Human Anatomy and Histology, Faculty of Medicine, University of Salamanca, Salamanca, Spain
- Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León, and Laboratory of Neuroendocrinology and Obesity of IBSAL, University of Salamanca, Salamanca, Spain
- * E-mail:
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Kühnen P, Matthae R, Arya V, Hauptmann K, Rothe K, Wächter S, Singer M, Mohnike W, Eberhard T, Raile K, Lauffer LM, Iakoubov R, Hussain K, Blankenstein O. Occurrence of giant focal forms of congenital hyperinsulinism with incorrect visualization by (18) F DOPA-PET/CT scanning. Clin Endocrinol (Oxf) 2014; 81:847-54. [PMID: 24750227 DOI: 10.1111/cen.12473] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Revised: 01/09/2014] [Accepted: 04/14/2014] [Indexed: 11/29/2022]
Abstract
CONTEXT Congenital hyperinsulinism (CHI) is a rare disease characterized by severe hypoglycaemic episodes due to pathologically increased insulin secretion from the pancreatic beta cells. When untreated, CHI might result in irreversible brain damage and death. Currently, two major subtypes of CHI are known: a focal form, associated with local distribution of affected beta cells and a nonfocal form, affecting every single beta cell. The identification of focal forms is important, as the patients can be cured by limited surgery. (18) F DOPA-PET/CT is an established non-invasive approach to differentiate focal from nonfocal CHI. OBJECTIVE The purpose of this study was to identify possible limitations of (18) F DOPA-PET/CT scan in patients with focal forms nonfocal CHI. DESIGN A retrospective chart review of 32 patients (from 2008 through 2013) who underwent (18) F DOPA-PET/CT and partial pancreatectomy for focal CHI at the reference centres in Berlin, Germany and London, UK. RESULTS In most cases (n = 29, 90·7%), (18) F DOPA-PET/CT was sufficient to localize the complete focal lesion. However, in some patients (n = 3, 9·3%), (18) F DOPA-PET/CT wrongly visualized only a small portion of the focal lesion. In this group of patients, a so-called 'giant focus' was detected in histopathological analysis during the surgery. CONCLUSIONS Our data show that in most patients with focal CHI (18) F DOPA-PET/CT correctly predicts the size and anatomical localisation of the lesion. However, in those patients with a 'giant focal' lesion (18) F DOPA-PET/CT is unreliable for correct identification of 'giant focus' cases.
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Affiliation(s)
- Peter Kühnen
- Institut für experimentelle pädiatrische Endokrinologie, Charité Universitätsmedizin, Berlin, Germany
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Montravers F, Arnoux JB, Ribeiro MJ, Kerrou K, Nataf V, Galmiche L, Aigrain Y, Bellanné-Chantelot C, Saint-Martin C, Ohnona J, Balogova S, Huchet V, Michaud L, Talbot JN, de Lonlay P. Strengths and limitations of using 18fluorine-fluorodihydroxyphenylalanine PET/CT for congenital hyperinsulinism. Expert Rev Endocrinol Metab 2014; 9:477-485. [PMID: 30736210 DOI: 10.1586/17446651.2014.949240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
18fluorine-fluorodihydroxyphenylalanine (FDOPA) PET/CT is currently the first-line imaging technique to distinguish between focal and diffuse forms of congenital hyperinsulinism (CHI) and to accurately localize focal forms. However, this technique has a number of limitations, mainly the very small size of focal forms or inversely a very large focal form mimicking a diffuse form, and misinterpretation of physiologic uptake masking hot spots or inversely mimicking focal forms. The other limitation is the limited availability of the radiopharmaceutical. FDOPA PET/CT has no recognized competitor to date among the available morphologic and functional imaging techniques. Other potential approaches using specific tracers for positron emission tomography (PET) are discussed, using radiopharmaceuticals specific for β cell mass or targeting somatostatin receptors. These radiopharmaceuticals can be labeled with gallium-68, a PET emitter readily available in PET centers equipped with 68Ge/68Ga generators.
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Affiliation(s)
- Françoise Montravers
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Baptiste Arnoux
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Maria-Joao Ribeiro
- c Service de médecine nucléaire, CHRU, Université François Rabelais, INSERM U930, Tours, France
| | - Khaldoun Kerrou
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Valérie Nataf
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Louise Galmiche
- d Service d'anatomo-pathologie, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Yves Aigrain
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Christine Bellanné-Chantelot
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Cécile Saint-Martin
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jessica Ohnona
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Sona Balogova
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
- f Department of nuclear medicine, Comenius University and St. Elisabeth Institute, Bratislava, Slovakia
| | - Virginie Huchet
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Laure Michaud
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Noël Talbot
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Pascale de Lonlay
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
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Gopal-Kothandapani JS, Hussain K. Congenital hyperinsulinism: Role of fluorine-18L-3, 4 hydroxyphenylalanine positron emission tomography scanning. World J Radiol 2014; 6:252-260. [PMID: 24976928 PMCID: PMC4072812 DOI: 10.4329/wjr.v6.i6.252] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/19/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Congenital hyperinsulinism (CHI) is a rare but complex heterogeneous disorder caused by unregulated secretion of insulin from the β-cells of the pancreas leading to severe hypoglycaemia and neuroglycopaenia. Swift diagnosis and institution of appropriate management is crucial to prevent or minimise adverse neurodevelopmental outcome in children with CHI. Histologically there are two major subtypes of CHI, diffuse and focal disease and the management approach will significantly differ depending on the type of the lesion. Patients with medically unresponsive diffuse disease require a near total pancreatectomy, which then leads on to the development of iatrogenic diabetes mellitus and pancreatic exocrine insufficiency. However patients with focal disease only require a limited pancreatectomy to remove only the focal lesion thus providing complete cure to the patient. Hence the preoperative differentiation of the histological subtypes of CHI becomes paramount in the management of CHI. Fluorine-18L-3, 4-hydroxyphenylalanine positron emission tomography (18F-DOPA-PET) is now the gold standard for pre-operative differentiation of focal from diffuse disease and localisation of the focal lesion. The aim of this review article is to give a clinical overview of CHI, then review the role of dopamine in β-cell physiology and finally discuss the role of 18F-DOPA-PET imaging in the management of CHI.
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Distinctive expression and cellular distribution of dopamine receptors in the pancreatic islets of rats. Cell Tissue Res 2014; 357:597-606. [DOI: 10.1007/s00441-014-1894-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 04/10/2014] [Indexed: 11/27/2022]
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VMAT2 identified as a regulator of late-stage β-cell differentiation. Nat Chem Biol 2013; 10:141-8. [PMID: 24316738 DOI: 10.1038/nchembio.1410] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 10/15/2013] [Indexed: 02/06/2023]
Abstract
Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated β-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.
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6-[18F]fluoro-L-DOPA uptake in the rat pancreas is dependent on the tracer metabolism. Mol Imaging Biol 2013; 16:403-11. [PMID: 24217945 DOI: 10.1007/s11307-013-0701-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 10/08/2013] [Accepted: 10/17/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE 6-[(18)F]fluoro-L-3,4-dihydroxyphenyl alanine ([(18)F]FDOPA) positron emission tomography (PET) is a diagnostic tool which can detect malignancies of the pancreas. We aimed to study whether the manipulation of the [(18)F]FDOPA metabolic pathway would change the (18)F-behavior to provide a biochemical foundation for PET imaging of rat pancreas with [(18)F]FDOPA. PROCEDURES Inhibitors of aromatic amino acid decarboxylase, catechol-O-methyltransferase, monoamine oxidases A and B, or their combinations on [(18)F]FDOPA uptake, metabolism, and the regional distribution in the rat pancreas was evaluated using in vivo PET/computed tomography imaging, chromatographic metabolite analyses, and autoradiography. RESULTS Enzyme inhibition generally increased the uptake of [(18)F]FDOPA derived (18)F-radioactivity in rat pancreas. Dependent on which enzymatic pathway is blocked (or a combination of pathways), different radiolabeled metabolites in pancreas are responsible for this increase in uptake. CONCLUSIONS Altering the metabolism of [(18)F]FDOPA by using various enzymatic inhibitors increased the radioactivity uptake and changed the radiometabolic profile in the pancreas allowing better discrimination between pancreas and surrounding tissues of rat. However, these manipulations did not separate islets from the exocrine pancreas. Elucidating the metabolic behavior of [(18)F]FDOPA provides a biochemical foundation of PET imaging of the rat pancreas.
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Ustione A, Piston DW, Harris PE. Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet. Mol Endocrinol 2013; 27:1198-207. [PMID: 23744894 DOI: 10.1210/me.2013-1083] [Citation(s) in RCA: 78] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Exogenous dopamine inhibits insulin secretion from pancreatic β-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the β-cells from circulating L-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, L-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an "antiincretin" signal that counterbalances the stimulatory effect of glucagon-like peptide 1.
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Affiliation(s)
- Alessandro Ustione
- Department of Molecular Physiology and Biophysics, Vanderbilt University, 702 Light Hall, Nashville, Tennessee 37232-0615, USA
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Banerjee I, Avatapalle B, Padidela R, Stevens A, Cosgrove KE, Clayton PE, Dunne MJ. Integrating genetic and imaging investigations into the clinical management of congenital hyperinsulinism. Clin Endocrinol (Oxf) 2013; 78:803-13. [PMID: 23347463 DOI: 10.1111/cen.12153] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 01/03/2013] [Accepted: 01/14/2013] [Indexed: 11/27/2022]
Abstract
Congenital Hyperinsulinism (CHI) is a rare but important cause of hypoglycaemia in infancy. CHI is a heterogeneous disease, but has a strong genetic basis; a number of genetic causes have been identified with CHI in about a third of individuals, chiefly in the genes that code for the ATP sensitive K(+) channels (KATP ) in the pancreatic β-cells. Rapid KATP channel gene testing is a critical early step in the diagnostic algorithm of CHI, with paternal heterozygosity correlating with the occurrence of focal lesions. Imaging investigations to diagnose and localize solitary pancreatic foci have evolved over the last decade with (18)F-DOPA PET-CT scanning as the current diagnostic tool of choice. Although clinical management of CHI has improved significantly with the application of genetic screening and imaging investigations, much remains to be uncovered. This includes a better understanding of the molecular mechanisms for dysregulated insulin release in those patients without known genetic mutations, and the development of biomarkers that could characterize CHI, including long-term prognosis and targeted treatment planning, i.e. 'personalised medicine'. From the perspective of pancreatic imaging, it would be important to achieve greater specificity of diagnosis not only for focal lesions but also for diffuse and atypical forms of the disease.
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Affiliation(s)
- I Banerjee
- Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, UK.
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Tuomela J, Forsback S, Haavisto L, Vahlberg T, Grönroos TJ, Solin O, Haaparanta-Solin M. Enzyme inhibition of dopamine metabolism alters 6-[18F]FDOPA uptake in orthotopic pancreatic adenocarcinoma. EJNMMI Res 2013; 3:18. [PMID: 23497589 PMCID: PMC3618317 DOI: 10.1186/2191-219x-3-18] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 02/24/2013] [Indexed: 02/04/2023] Open
Abstract
Background An unknown location hampers removal of pancreatic tumours. We studied the effects of enzyme inhibitors on the uptake of 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the pancreas, aiming at improved imaging of pancreatic adenocarcinoma. Methods Mice bearing orthotopic BxPC3 pancreatic adenocarcinoma were injected with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and scanned with positron emission tomography/computed tomography (PET/CT). For [18F]FDOPA studies, tumour-bearing mice and sham-operated controls were pretreated with enzyme inhibitors of aromatic amino acid decarboxylase (AADC), catechol-O-methyl transferase (COMT), monoamine oxidase A (MAO-A) or a combination of COMT and MAO-A. Mice were injected with [18F]FDOPA and scanned with PET/CT. The absolute [18F]FDOPA uptake was determined from selected tissues using a gamma counter. The intratumoural biodistribution of [18F]FDOPA was recorded by autoradiography. The main [18F]FDOPA metabolites present in the pancreata were determined with radio-high-performance liquid chromatography. Results [18F]FDG uptake was high in pancreatic tumours, while [18F]FDOPA uptake was highest in the healthy pancreas and significantly lower in tumours. [18F]FDOPA uptake in the pancreas was lowest with vehicle pretreatment and highest with pretreatment with the inhibitor of AADC. When mice received COMT + MAO-A inhibitors, the uptake was high in the healthy pancreas but low in the tumour-bearing pancreas. Conclusions Combined use of [18F]FDG and [18F]FDOPA is suitable for imaging pancreatic tumours. Unequal pancreatic uptake after the employed enzyme inhibitors is due to the blockade of metabolism and therefore increased availability of [18F]FDOPA metabolites, in which uptake differs from that of [18F]FDOPA. Pretreatment with COMT + MAO-A inhibitors improved the differentiation of pancreas from the surrounding tissue and healthy pancreas from tumour. Similar advantage was not achieved using AADC enzyme inhibitor, carbidopa.
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Affiliation(s)
- Johanna Tuomela
- MediCity/PET Preclinical Imaging, Turku PET Centre, University of Turku, Turku, 20520, Finland.
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35
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Di Gialleonardo V, de Vries EFJ, Di Girolamo M, Quintero AM, Dierckx RAJO, Signore A. Imaging of β-cell mass and insulitis in insulin-dependent (Type 1) diabetes mellitus. Endocr Rev 2012; 33:892-919. [PMID: 22889646 DOI: 10.1210/er.2011-1041] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Insulin-dependent (type 1) diabetes mellitus is a metabolic disease with a complex multifactorial etiology and a poorly understood pathogenesis. Genetic and environmental factors cause an autoimmune reaction against pancreatic β-cells, called insulitis, confirmed in pancreatic samples obtained at autopsy. The possibility to noninvasively quantify β-cell mass in vivo would provide important biological insights and facilitate aspects of diagnosis and therapy, including follow-up of islet cell transplantation. Moreover, the availability of a noninvasive tool to quantify the extent and severity of pancreatic insulitis could be useful for understanding the natural history of human insulin-dependent (type 1) diabetes mellitus, to early diagnose children at risk to develop overt diabetes, and to select patients to be treated with immunotherapies aimed at blocking the insulitis and monitoring the efficacy of these therapies. In this review, we outline the imaging techniques currently available for in vivo, noninvasive detection of β-cell mass and insulitis. These imaging techniques include magnetic resonance imaging, ultrasound, computed tomography, bioluminescence and fluorescence imaging, and the nuclear medicine techniques positron emission tomography and single-photon emission computed tomography. Several approaches and radiopharmaceuticals for imaging β-cells and lymphocytic insulitis are reviewed in detail.
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Affiliation(s)
- Valentina Di Gialleonardo
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, 9700 AB, Groningen, The Netherlands
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Abstract
Here, we outline how islet cells use autocrine and paracrine 'circuits' of classical neurotransmitters and their corresponding receptors and transporters to communicate with vicinal β-cells to regulate glucose-stimulated insulin secretion. Many of these same circuits operate in the central nervous system and can be visualized by molecular imaging. We discuss how these techniques might be applied to measuring the dynamics of β-cell function in real time.
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Affiliation(s)
- P E Harris
- Division of Endocrinology, Department of Medicine, The Naomi Berrie Diabetes Center and Columbia University College of Physicians and Surgeons, New York, NY, USA.
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37
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Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic β-cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. Mol Endocrinol 2012; 26:1928-40. [PMID: 22918877 DOI: 10.1210/me.2012-1226] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Pancreatic islets are critical for glucose homeostasis via the regulated secretion of insulin and other hormones. We propose a novel mechanism that regulates insulin secretion from β-cells within mouse pancreatic islets: a dopaminergic negative feedback acting on insulin secretion. We show that islets are a site of dopamine synthesis and accumulation outside the central nervous system. We show that both dopamine and its precursor l-dopa inhibit glucose-stimulated insulin secretion, and this inhibition correlates with a reduction in frequency of the intracellular [Ca(2+)] oscillations. We further show that the effects of dopamine are abolished by a specific antagonist of the dopamine receptor D3. Because the dopamine transporter and dopamine receptors are expressed in the islets, we propose that cosecretion of dopamine with insulin activates receptors on the β-cell surface. D3 receptor activation results in changes in intracellular [Ca(2+)] dynamics, which, in turn, lead to lowered insulin secretion. Because blocking dopaminergic negative feedback increases insulin secretion, expanding the knowledge of this pathway in β-cells might offer a potential new target for the treatment of type 2 diabetes.
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Affiliation(s)
- Alessandro Ustione
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee 37232-0615, USA
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38
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Simpson N, Maffei A, Freeby M, Burroughs S, Freyberg Z, Javitch J, Leibel RL, Harris PE. Dopamine-mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol 2012; 26:1757-72. [PMID: 22915827 DOI: 10.1210/me.2012-1101] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
We describe a negative feedback autocrine regulatory circuit for glucose-stimulated insulin secretion in purified human islets in vitro. Using chronoamperometry and in vitro glucose-stimulated insulin secretion measurements, evidence is provided that dopamine (DA), which is loaded into insulin-containing secretory granules by vesicular monoamine transporter type 2 in human β-cells, is released in response to glucose stimulation. DA then acts as a negative regulator of insulin secretion via its action on D2R, which are also expressed on β-cells. We found that antagonism of receptors participating in islet DA signaling generally drive increased glucose-stimulated insulin secretion. These in vitro observations may represent correlates of the in vivo metabolic changes associated with the use of atypical antipsychotics, such as increased adiposity.
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Affiliation(s)
- Norman Simpson
- Division of Endocrinology, Department of Medicine, Columbia University Medical College, 650 West 168th Street, BB 2006, New York, New York 10032, USA
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39
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Abstract
Congenital hyperinsulinism is a leading cause of severe hypoglycaemia in the newborn period. There are two (diffuse and focal) histological subtypes of congenital hyperinsulinism. The diffuse form affects the entire pancreas and if medically unresponsive will require a near total (95%-98%) pancreatectomy. The focal form affects only a small region of the pancreas (with the rest of the pancreas being normal in endocrine and exocrine function) and only requires a limited pancreatectomy. This limited section of the focal lesion has the potential for curing the patient. Thus the pre-operative differentiation of these two subgroups is extremely important. Recent advances in Fluorine-18-L-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET/CT) have radically changed the clinical approach to patient with congenital hyperinsulinism. In most patients this novel imaging technique is able to offer precise pre-operative localisation of the focal lesion, thus guiding the extent of surgical resection.
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Affiliation(s)
- Dunia Ismail
- Clinical and Molecular Genetics Unit, The Developmental Endocrinology Research Group, Institute of Child Health, University College London, Great Ormond Street Hospital for Children NHS Trust, 30 Guilford Street, London, WC1N 1EH, UK
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40
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Abstract
In both type 1 and type 2 diabetes mellitus, beta-cell mass (BCM), which exclusively produces insulin, is lost. Various therapeutic strategies are being developed that target BCM to restore its function by promoting beta-cell neogenesis and regeneration or by preventing its apoptosis. To this end, it is essential to identify biomarkers of BCM. Of the various imaging platforms, radionuclide-based imaging methods using radioligands that directly target BCM appear promising. In particular, the vesicular monoamine transporter type 2 (VMAT2), which is expressed almost exclusively by beta-cells and found in close association with insulin, can be noninvasively imaged with PET and (11)C-dihydrotetrabenazine or its derivatives. Despite the major limitation that beta-cells are low in abundance (1%-2%) and dispersed throughout the pancreas, VMAT2 PET is sensitive enough to detect VMAT2 signal and to allow kinetic model-based quantification of VMAT2 binding within the pancreas. However, these techniques are still in early stages, and careful further evaluations and technical developments are needed before they can be clinically used as a valid biomarker of BCM.
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Affiliation(s)
- Masanori Ichise
- Department of Radiology, Columbia University Medical College, New York, New York 11032, USA.
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41
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García-Tornadú I, Ornstein AM, Chamson-Reig A, Wheeler MB, Hill DJ, Arany E, Rubinstein M, Becu-Villalobos D. Disruption of the dopamine d2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology 2010; 151:1441-50. [PMID: 20147524 DOI: 10.1210/en.2009-0996] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The relationship between antidopaminergic drugs and glucose has not been extensively studied, even though chronic neuroleptic treatment causes hyperinsulinemia in normal subjects or is associated with diabetes in psychiatric patients. We sought to evaluate dopamine D2 receptor (D2R) participation in pancreatic function. Glucose homeostasis was studied in D2R knockout mice (Drd2(-/-)) mice and in isolated islets from wild-type and Drd2(-/-) mice, using different pharmacological tools. Pancreas immunohistochemistry was performed. Drd2(-/-) male mice exhibited an impairment of insulin response to glucose and high fasting glucose levels and were glucose intolerant. Glucose intolerance resulted from a blunted insulin secretory response, rather than insulin resistance, as shown by glucose-stimulated insulin secretion tests (GSIS) in vivo and in vitro and by a conserved insulin tolerance test in vivo. On the other hand, short-term treatment with cabergoline, a dopamine agonist, resulted in glucose intolerance and decreased insulin response to glucose in wild-type but not in Drd2(-/-) mice; this effect was partially prevented by haloperidol, a D2R antagonist. In vitro results indicated that GSIS was impaired in islets from Drd2(-/-) mice and that only in wild-type islets did dopamine inhibit GSIS, an effect that was blocked by a D2R but not a D1R antagonist. Finally, immunohistochemistry showed a diminished pancreatic beta-cell mass in Drd2(-/-) mice and decreased beta-cell replication in 2-month-old Drd2(-/-) mice. Pancreatic D2Rs inhibit glucose-stimulated insulin release. Lack of dopaminergic inhibition throughout development may exert a gradual deteriorating effect on insulin homeostasis, so that eventually glucose intolerance develops.
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Affiliation(s)
- Isabel García-Tornadú
- Instituto de Biología y Medicina Experimental-CONICET, Vuelta de Obligado 2490, Buenos Aires 1428, Argentina.
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Freeby M, Goland R, Ichise M, Maffei A, Leibel R, Harris P. VMAT2 quantitation by PET as a biomarker for beta-cell mass in health and disease. Diabetes Obes Metab 2008; 10 Suppl 4:98-108. [PMID: 18834437 DOI: 10.1111/j.1463-1326.2008.00943.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The common pathology underlying both type 1 and type 2 diabetes (T1DM and T2DM) is insufficient beta-cell mass (BCM) to meet metabolic demands. An important impediment to the more rapid evaluation of interventions for both T1DM and T2DM lack of biomarkers of pancreatic BCM. A reliable means of monitoring the mass and/or function of beta-cells would enable evaluation of the progression of diabetes as well as the monitoring of pharmacologic and other interventions. Recently, we identified a biomarker of BCM that is quantifiable by positron emission tomography (PET). PET is an imaging technique which allows for non-invasive measurements of radioligand uptake and clearance, is sensitive in the pico- to nanomolar range and of which the results can be deconvoluted into measurements of receptor concentration. For BCM estimates, we have identified VMAT2 (vesicular monoamine transporter type 2) as a biomarker and [(11)C] DTBZ (dihydrotetrabenazine) as the transporter's ligand. VMAT2 is highly expressed in beta-cells of the human pancreas relative to other cells of the endocrine and exocrine pancreas. Thus measurements of [(11)C] DTBZ in the pancreas provide an indirect measurement of BCM. Here we summarize our ongoing efforts to validate the clinical utility of this non-invasive approach to real-time BCM measurements.
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Affiliation(s)
- M Freeby
- Department of Medicine of Columbia University Medical Center, New York, NY, USA
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43
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Raffo A, Hancock K, Polito T, Andan G, Witkowski P, Hardy M, Barba P, Ferrara C, Maffei A, Freeby M, Goland R, Leibel RL, Sweet I, Harris PE. Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine. J Endocrinol 2008; 198:41-9. [PMID: 18577569 PMCID: PMC2712213 DOI: 10.1677/joe-07-0632] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Despite different embryological origins, islet beta-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human beta-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by beta-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous L-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in beta-cells.
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Affiliation(s)
- Anthony Raffo
- Department of Medicine of Columbia University Medical Center, New York, NY, 10032, USA
| | - Kolbe Hancock
- Barnard College, Columbia University, New York, NY 10027, USA
| | - Teresa Polito
- Department of Medicine of Columbia University Medical Center, New York, NY, 10032, USA
| | - Gordon Andan
- Department of Surgery of Columbia University Medical Center, New York, NY, 10032, USA
| | - Piotr Witkowski
- Department of Surgery of Columbia University Medical Center, New York, NY, 10032, USA
- Dept of Surgery, Medical University of Gdansk, Poland
| | - Mark Hardy
- Department of Surgery of Columbia University Medical Center, New York, NY, 10032, USA
| | - Pasquale Barba
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, 80131, Italy
| | - Caterina Ferrara
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, 80131, Italy
| | - Antonella Maffei
- Department of Medicine of Columbia University Medical Center, New York, NY, 10032, USA
- Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Naples, 80131, Italy
| | - Matthew Freeby
- Department of Medicine of Columbia University Medical Center, New York, NY, 10032, USA
| | - Robin Goland
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Rudolph L. Leibel
- Naomi Berrie Diabetes Center, Columbia University Medical Center, New York, NY 10032, USA
| | - Ian Sweet
- Department of Medicine, University of Washington, Seattle, WA 98195, USA
| | - Paul E. Harris
- Department of Medicine of Columbia University Medical Center, New York, NY, 10032, USA
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44
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Schober AK, Hahn EG, Harsch IA. [A 67-year-old patient with recurrent hypoglycemia]. Internist (Berl) 2008; 49:485-9. [PMID: 18324381 DOI: 10.1007/s00108-008-2046-7] [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: 11/25/2022]
Abstract
A 67 year old female patient was admitted to our clinic with recurrent hypoglycemia in December 2006. Laboratory findings revealed an elevated insulin, and C-peptide. Imaging techniques revealed a tumor of the pancreas involving the spleen with metastases of the liver, expressing somatostatin receptors. Ultrasound-guided biopsy was performed and confirmed the suspected insulinoma. Since the hypoglycemias could not sufficiently be controlled by subcutaneous administration of octreotide and by oral glucose intake, surgical debulking was performed in a palliative intention. After resection the patient was free of hypoglycemia. In case of diagnosed insulinoma, underlying MEN (multiple endocrine neoplasia) should be considered. Excision of the tumor is recommended in patients with benign solitary insulinomas. If complete excision is impossible, there are several therapeutic options that aim at preventing hypoglycemia. Thus, in contrast to other extended tumors, surgery is reasonable in malignant insulinoma even in case of metastatic disease.
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Affiliation(s)
- A K Schober
- Schwerpunkt Endokrinologie und Stoffwechsel, Medizinische Klinik I, Friedrich-Alexander Universität, Ulmenweg 18, 91054, Erlangen, Germany
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45
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Palladino AA, Bennett MJ, Stanley CA. Hyperinsulinism in Infancy and Childhood: When an Insulin Level Is Not Always Enough. Clin Chem 2008; 54:256-63. [DOI: 10.1373/clinchem.2007.098988] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Abstract
Background: Hypoglycemia in infants and children can lead to seizures, developmental delay, and permanent brain damage. Hyperinsulinism (HI) is the most common cause of both transient and permanent disorders of hypoglycemia. HI is characterized by dysregulated insulin secretion, which results in persistent mild to severe hypoglycemia. The various forms of HI represent a group of clinically, genetically, and morphologically heterogeneous disorders.
Content: Congenital hyperinsulinism is associated with mutations of SUR-1 and Kir6.2, glucokinase, glutamate dehydrogenase, short-chain 3-hydroxyacyl-CoA dehydrogenase, and ectopic expression on β-cell plasma membrane of SLC16A1. Hyperinsulinism can be associated with perinatal stress such as birth asphyxia, maternal toxemia, prematurity, or intrauterine growth retardation, resulting in prolonged neonatal hypoglycemia. Mimickers of hyperinsulinism include neonatal panhypopituitarism, drug-induced hypoglycemia, insulinoma, antiinsulin and insulin-receptor stimulating antibodies, Beckwith-Wiedemann Syndrome, and congenital disorders of glycosylation. Laboratory testing for hyperinsulinism may include quantification of blood glucose, plasma insulin, plasma β-hydroxybutyrate, plasma fatty acids, plasma ammonia, plasma acylcarnitine profile, and urine organic acids. Genetic testing is available through commercial laboratories for genes known to be associated with hyperinsulinism. Acute insulin response (AIR) tests are useful in phenotypic characterization. Imaging and histologic tools are also available for diagnosing and classifying hyperinsulinism. The goal of treatment in infants with hyperinsulinism is to prevent brain damage from hypoglycemia by maintaining plasma glucose levels above 700 mg/L (70 mg/dL) through pharmacologic or surgical therapy.
Summary: The management of hyperinsulinism requires a multidisciplinary approach that includes pediatric endocrinologists, radiologists, surgeons, and pathologists who are trained in diagnosing, identifying, and treating hyperinsulinism.
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Affiliation(s)
| | - Michael J Bennett
- The Children’s Hospital of Philadelphia, Division of Endocrinology, Philadelphia, PA
| | - Charles A Stanley
- The Children’s Hospital of Philadelphia, Division of Endocrinology, Philadelphia, PA
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Weizhen Wu, Jin Shang, Yue Feng, Thompson CM, Horwitz S, Thompson JR, Macintyre ED, Thornberry NA, Chapman K, Zhou YP, Howard AD, Jing Li. Identification of Glucose-Dependent Insulin Secretion Targets in Pancreatic β Cells by Combining Defined-Mechanism Compound Library Screening and siRNA Gene Silencing. ACTA ACUST UNITED AC 2008; 13:128-34. [DOI: 10.1177/1087057107313763] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Identification and validation of novel drug targets continues to be a major bottleneck in drug development, particularly for polygenic complex diseases such as type 2 diabetes. Here, the authors describe an approach that allows researchers to rapidly identify and validate potential drug targets by combining chemical tools and RNA interference technology. As a proof-of-concept study, the known mechanism Sigma LOPAC library was used to screen for glucose-dependent insulin secretion (GDIS) in INS-1 832/13 cells. In addition to several mechanisms that are known to regulate GDIS (such as cyclic adenosine monophosphate—specific phosphodiesterases, adrenoceptors, and Ca2+ channels), the authors find that several of the dopamine receptor ( DRD) antagonists significantly enhance GDIS, whereas DRD agonists profoundly inhibit GDIS. Subsequent siRNA studies in the same cell line indicate that knockdown of DRD2 enhanced GDIS. Furthermore, selective DRD2 antagonists and agonists also enhance or suppress, respectively, GDIS in isolated rat islets. The data support that the approach described here offers a rapid and effective way for target identification and validation. ( Journal of Biomolecular Screening 2008;128-134)
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Affiliation(s)
| | - Jin Shang
- Merck Research Laboratories, Rahway, NJ
| | - Yue Feng
- Merck Research Laboratories, Rahway, NJ
| | | | | | | | | | | | | | | | | | - Jing Li
- Merck Research Laboratories, Rahway, NJ,
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Durant S, Coulaud J, Homo-Delarche F. Bromocriptine-induced hyperglycemia in nonobese diabetic mice: kinetics and mechanisms of action. Rev Diabet Stud 2007; 4:185-94. [PMID: 18084676 PMCID: PMC2174061 DOI: 10.1900/rds.2007.4.185] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
The effects of bromocriptine (10 mg/kg), known to inhibit prolactin secretion and lower autoimmune processes, were studied on glucose homeostasis in non-fasted non-obese diabetic mice, a spontaneous model of type 1 diabetes. Hyperglycemia was observed 120 and 240 min after i.p. but not s.c. injection. Bromocriptine administration i.p. led to rapid and marked hyperglycemia characterized by sexual dimorphism with males having higher glycemia than females. Bromocriptine induced a rapid but transient decrease in insulinemia in males only and biphasic increases in glucagon levels and a sustained stimulatory effect on circulating corticosterone in both sexes. Bromocriptine-induced hyperglycemia involved D2-dopaminergic receptors, as demonstrated by the inhibitory effect of the D2-dopamine antagonist, metoclopramide (10 mg/kg). Simultaneous injection of bromocriptine and metoclopramide also blocked the rise in blood corticosterone. In conclusion, by inducing hyperglycemia, i.p. bromocriptine administration to prediabetic autoimmune mice may counteract its beneficial anti-immunostimulatory effects.
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Affiliation(s)
- Sylvie Durant
- INSERM U530, Centre Universitaire-UFR biomedicale, 45, rue des Saints-Peres, 75006 Paris, France
| | - Josiane Coulaud
- CNRS UMR 7059, Universite Paris 7 / D. Diderot, 2, place Jussieu, 75271 Paris Cedex 05, France
| | - Francoise Homo-Delarche
- CNRS UMR 7059, Universite Paris 7 / D. Diderot, 2, place Jussieu, 75271 Paris Cedex 05, France
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48
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Harris PE, Ferrara C, Barba P, Polito T, Freeby M, Maffei A. VMAT2 gene expression and function as it applies to imaging beta-cell mass. J Mol Med (Berl) 2007; 86:5-16. [PMID: 17665159 DOI: 10.1007/s00109-007-0242-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2007] [Revised: 06/06/2007] [Accepted: 06/27/2007] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. The two main forms of the disease are distinguished by different pathogenesis, natural histories, and population distributions and indicated as either type 1 (T1DM) or type 2 diabetes mellitus (T2DM). It is well established that T1DM is an autoimmune disease whereby beta-cells of pancreatic islets are destroyed leading to loss of endogenous insulin production. Albeit less dramatic, beta-cell mass (BCM) also drops in T2DM. Therefore, it is realistic to expect that noninvasive measures of BCM might provide useful information in the diabetes-care field. Preclinical studies have demonstrated that BCM measurements by positron emission tomography scanning, using the vesicular monoamine transporter type 2 (VMAT2) as a tissue-specific surrogate marker of insulin production and [11C] Dihydrotetrabenazine (DTBZ) as the radioligand specific for this molecule, is feasible in animal models. Unfortunately, the mechanisms underlying beta-cell-specific expression of VMAT2 are still largely unexplored, and a much better understanding of the regulation of VMAT2 gene expression and of its function in beta-cells will be required before the full utility of this technique in the prediction and treatment of individuals with diabetes can be understood. In this review, we summarize much of what is understood about the regulation of VMAT2 and identify questions whose answers may help in understanding what measurements of VMAT2 density mean in the context of diabetes.
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Affiliation(s)
- Paul E Harris
- Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, Naples, Italy.
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Kauhanen S, Seppänen M, Minn H, Gullichsen R, Salonen A, Alanen K, Parkkola R, Solin O, Bergman J, Sane T, Salmi J, Välimäki M, Nuutila P. Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography as a tool to localize an insulinoma or beta-cell hyperplasia in adult patients. J Clin Endocrinol Metab 2007; 92:1237-44. [PMID: 17227804 DOI: 10.1210/jc.2006-1479] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT AND OBJECTIVE Fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) is a promising method in localizing neuroendocrine tumors. Recently, it has been shown to differentiate focal forms of congenital hyperinsulinism of infancy. The current study was set up to determine the potential of 18F-DOPA PET in identifying the insulin-secreting tumors or beta-cell hyperplasia of the pancreas in adults. PATIENTS AND METHODS We prospectively studied 10 patients with confirmed hyperinsulinemic hypoglycemia and presumed insulin-secreting tumor using 18F-DOPA PET. Anatomical imaging was performed with computed tomography (CT) and magnetic resonance imaging (MRI). All patients were operated on, and histological verification was available in each case. Semiquantitative PET findings in the pancreas using standardized uptake values were compared to standardized uptake values of seven consecutive patients with nonpancreatic neuroendocrine tumors. RESULTS By visual inspection of 18F-DOPA PET images, it was possible in nine of 10 patients to localize the pancreatic lesion, subsequently confirmed by histological analysis. 18F-DOPA uptake was enhanced in six of seven solid insulinomas and in the malignant insulinoma and its hepatic metastasis. Two patients with beta-cell hyperplasia showed increased focal uptake of 18F-DOPA in the affected areas. As compared to CT or MRI, 18F-DOPA PET was more sensitive in localizing diseased pancreatic tissue. CONCLUSION 18F-DOPA PET was useful in most patients with insulinoma and negative CT, MRI, and ultrasound results. In agreement with previous findings in infants, preoperative 18F-DOPA imaging seems to be a method of choice for the detection of beta-cell hyperplasia in adults. It should be considered for the detection of insulinoma or beta-cell hyperplasia in patients with confirmed hyperinsulinemic hypoglycemias when other diagnostic work-up is negative.
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Affiliation(s)
- Saila Kauhanen
- Turku PET Centre, Department of Surgery, Turku University Hospital, P.O. Box 52, FIN-20521 Turku, Finland
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De León DD, Stanley CA. Mechanisms of Disease: advances in diagnosis and treatment of hyperinsulinism in neonates. ACTA ACUST UNITED AC 2007; 3:57-68. [PMID: 17179930 DOI: 10.1038/ncpendmet0368] [Citation(s) in RCA: 153] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2006] [Accepted: 08/25/2006] [Indexed: 11/09/2022]
Abstract
Hyperinsulinism is the single most common mechanism of hypoglycemia in neonates. Dysregulated insulin secretion is responsible for the transient and prolonged forms of neonatal hypoglycemia, and congenital genetic disorders of insulin regulation represent the most common of the permanent disorders of hypoglycemia. Mutations in at least five genes have been associated with congenital hyperinsulinism: they encode glucokinase, glutamate dehydrogenase, the mitochondrial enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase, and the two components (sulfonylurea receptor 1 and potassium inward rectifying channel, subfamily J, member 11) of the ATP-sensitive potassium channels (K(ATP) channels). K(ATP) hyperinsulinism is the most common and severe form of congenital hyperinsulinism. Infants suffering from K(ATP) hyperinsulinism present shortly after birth with severe and persistent hypoglycemia, and the majority are unresponsive to medical therapy, thus requiring pancreatectomy. In up to 40-60% of the children with K(ATP) hyperinsulinism, the defect is limited to a focal lesion in the pancreas. In these children, local resection results in cure with avoidance of the complications inherent to a near-total pancreatectomy. Hyperinsulinism can also be part of other disorders such as Beckwith-Wiedemann syndrome and congenital disorders of glycosylation. The diagnosis and management of children with congenital hyperinsulinism requires a multidisciplinary approach to achieve the goal of therapy: prevention of permanent brain damage due to recurrent hypoglycemia.
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