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Vasilev G, Kokudeva M, Siliogka E, Padilla N, Shumnalieva R, Della-Morte D, Ricordi C, Mihova A, Infante M, Velikova T. T helper 17 cells and interleukin-17 immunity in type 1 diabetes: From pathophysiology to targeted immunotherapies. World J Diabetes 2025; 16:99936. [DOI: 10.4239/wjd.v16.i4.99936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 12/06/2024] [Accepted: 02/07/2025] [Indexed: 02/28/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells, which ultimately results in insulinopenia, hyperglycemia and lifelong need for exogenous insulin therapy. In the pathophysiological landscape of T1D, T helper 17 cells (Th17 cells) and their hallmark cytokine, interleukin (IL)-17, play pivotal roles from disease onset to disease progression. In this narrative mini-review, we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D, providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction. Furthermore, we summarized the main animal and clinical studies that investigated Th17- and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
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Affiliation(s)
- Georgi Vasilev
- Clinic of Neurology and Department of Emergency Medicine, UMHAT "Sv. Georgi", Plovdiv 4000, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Maria Kokudeva
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University of Sofia, Sofia 1000, Bulgaria
| | - Elina Siliogka
- Faculty of Medicine, National and Kapodistrian University of Athens, Athens 11527, Attikí, Greece
| | - Nathalia Padilla
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | - Russka Shumnalieva
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Rheumatology, Clinic of Rheumatology, University Hospital "St. Anna", Medical University-Sofia, Sofia 1612, Bulgaria
| | - David Della-Morte
- Department of Biomedicine and Prevention, Section of Clinical Nutrition and Nutrigenomics, University of Rome Tor Vergata, Rome 00133, Italy
| | - Camillo Ricordi
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, United States
| | | | - Marco Infante
- Section of Diabetes & Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Rome 00131, Italy
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Wagner LE, Melnyk O, Turner A, Duffett BE, Muralidharan C, Martinez-Irizarry MM, Arvin MC, Orr KS, Manduchi E, Kaestner KH, Brozinick JT, Linnemann AK. IFN-α Induces Heterogenous ROS Production in Human β-Cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.19.639120. [PMID: 40027743 PMCID: PMC11870469 DOI: 10.1101/2025.02.19.639120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Type 1 diabetes (T1D) is a multifactorial disease involving genetic and environmental factors, including viral infection. We investigated the impact of interferon alpha (IFN-α), a cytokine produced during the immune response to viral infection or the presence of un-edited endogenous double-stranded RNAs, on human β-cell physiology. Intravital microscopy on transplanted human islets using a β-cell-selective reactive oxygen species (ROS) biosensor (RIP1-GRX1-roGFP2), revealed a subset of human β-cells that acutely produce ROS in response to IFN-α. Comparison to Integrated Islet Distribution Program (IIDP) phenotypic data revealed that healthier donors had more ROS accumulating cells. I n vitro IFN-α treatment of human islets similarly elicited a heterogenous increase in superoxide production that originated in the mitochondria. To determine the unique molecular signature predisposing cells to IFN-α stimulated ROS production, we flow sorted human islets treated with IFN-α. RNA sequencing identified genes involved in inflammatory and immune response in the ROS-producing cells. Comparison with single cell RNA-Seq datasets available through the Human Pancreas Analysis Program (HPAP) showed that genes upregulated in ROS-producing cells are enriched in control β-cells rather than T1D donors. Combined, these data suggest that IFN-α stimulates mitochondrial ROS production in healthy human β-cells, potentially predicting a more efficient antiviral response.
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Affiliation(s)
- Leslie E. Wagner
- Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - Olha Melnyk
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Abigail Turner
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Bryce E. Duffett
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Charanya Muralidharan
- Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | | | - Matthew C. Arvin
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Kara S. Orr
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
| | - Elisabetta Manduchi
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA
| | - Klaus H. Kaestner
- Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, PA
| | | | - Amelia K. Linnemann
- Departments of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN
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3
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Krivova Y, Proshchina A, Otlyga D, Kharlamova A, Saveliev S. Detection of Insulin in Insulin-Deficient Islets of Patients with Type 1 Diabetes. Life (Basel) 2025; 15:125. [PMID: 39860066 PMCID: PMC11766825 DOI: 10.3390/life15010125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/14/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Type 1 diabetes (T1D) is related to the autoimmune destruction of β-cells, leading to their almost complete absence in patients with longstanding T1D. However, endogenous insulin secretion persists in such patients as evidenced by the measurement of plasma C-peptide. Recently, a low level of insulin has been found in non-β islet cells of patients with longstanding T1D, indicating that other islet cell types may contribute to persistent insulin secretion. The present study aimed to test the ability of various antibodies to detect insulin in insulin-deficient islets of T1D patients. Pancreatic autopsies from two children with recent-onset T1D, two adults with longstanding T1D, and three control subjects were examined using double immunofluorescent labeling with antibodies to insulin, glucagon and somatostatin. Immunoreactivity to insulin in glucagon+ cells of insulin-deficient islets was revealed using polyclonal antibodies and monoclonal antibodies simultaneously recognizing insulin and proinsulin. Along with this, immunoreactivity to insulin was observed in the majority of glucagon+ cells of insulin-containing islets of control subjects and children with recent-onset T1D. These results suggest that islet α-cells may contain insulin and/or other insulin-like proteins (proinsulin, C-peptide). Future studies are needed to evaluate the role of α-cells in insulin secretion and diabetes pathogenesis.
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Affiliation(s)
- Yuliya Krivova
- Laboratory of Nervous System Development, Avtsyn Research Institute of Human Morphology of Federal State Budgetary Scientific Institution “Petrovsky National Research Centre of Surgery”, Tsurupi Street, 3, 117418 Moscow, Russia; (A.P.); (D.O.); (A.K.); (S.S.)
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Rutter GA, Gresch A, Delgadillo Silva L, Benninger RKP. Exploring pancreatic beta-cell subgroups and their connectivity. Nat Metab 2024; 6:2039-2053. [PMID: 39117960 DOI: 10.1038/s42255-024-01097-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 07/05/2024] [Indexed: 08/10/2024]
Abstract
Functional pancreatic islet beta cells are essential to ensure glucose homeostasis across species from zebrafish to humans. These cells show significant heterogeneity, and emerging studies have revealed that connectivity across a hierarchical network is required for normal insulin release. Here, we discuss current thinking and areas of debate around intra-islet connectivity, cellular hierarchies and potential "controlling" beta-cell populations. We focus on methodologies, including comparisons of different cell preparations as well as in vitro and in vivo approaches to imaging and controlling the activity of human and rodent islet preparations. We also discuss the analytical approaches that can be applied to live-cell data to identify and study critical subgroups of cells with a disproportionate role in control Ca2+ dynamics and thus insulin secretion (such as "first responders", "leaders" and "hubs", as defined by Ca2+ responses to glucose stimulation). Possible mechanisms by which this hierarchy is achieved, its physiological relevance and how its loss may contribute to islet failure in diabetes mellitus are also considered. A glossary of terms and links to computational resources are provided.
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Affiliation(s)
- Guy A Rutter
- CHUM Research Center and Faculty of Medicine, University of Montréal, Montréal, QC, Canada.
- Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
| | - Anne Gresch
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Luis Delgadillo Silva
- CHUM Research Center and Faculty of Medicine, University of Montréal, Montréal, QC, Canada
| | - Richard K P Benninger
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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Golden GJ, Wu VH, Hamilton JT, Amses KR, Shapiro MR, Japp AS, Liu C, Pampena MB, Kuri-Cervantes L, Knox JJ, Gardner JS, Atkinson MA, Brusko TM, Prak ETL, Kaestner KH, Naji A, Betts MR. Immune perturbations in human pancreas lymphatic tissues prior to and after type 1 diabetes onset. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.23.590798. [PMID: 39345402 PMCID: PMC11429609 DOI: 10.1101/2024.04.23.590798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Autoimmune destruction of pancreatic β cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, β cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.
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Affiliation(s)
- Gregory J Golden
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Vincent H Wu
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jacob T Hamilton
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Kevin R Amses
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Melanie R Shapiro
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
| | - Alberto Sada Japp
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Chengyang Liu
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Maria Betina Pampena
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Leticia Kuri-Cervantes
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - James J Knox
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Jay S Gardner
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Mark A Atkinson
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Todd M Brusko
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL 32610, USA
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Eline T Luning Prak
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Ali Naji
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
| | - Michael R Betts
- Department of Microbiology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
- Institute for Immunology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA
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6
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Fuhri Snethlage CM, Balvers M, Ferwerda B, Rampanelli E, de Groen P, Roep BO, Herrema H, McDonald TJ, van Raalte DH, Weedon MN, Oram RA, Nieuwdorp M, Hanssen NMJ. Associations between diabetes-related genetic risk scores and residual beta cell function in type 1 diabetes: the GUTDM1 study. Diabetologia 2024; 67:1865-1876. [PMID: 38922416 PMCID: PMC11410997 DOI: 10.1007/s00125-024-06204-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/29/2024] [Indexed: 06/27/2024]
Abstract
AIMS/HYPOTHESIS Use of genetic risk scores (GRS) may help to distinguish between type 1 diabetes and type 2 diabetes, but less is known about whether GRS are associated with disease severity or progression after diagnosis. Therefore, we tested whether GRS are associated with residual beta cell function and glycaemic control in individuals with type 1 diabetes. METHODS Immunochip arrays and TOPMed were used to genotype a cross-sectional cohort (n=479, age 41.7 ± 14.9 years, duration of diabetes 16.0 years [IQR 6.0-29.0], HbA1c 55.6 ± 12.2 mmol/mol). Several GRS, which were originally developed to assess genetic risk of type 1 diabetes (GRS-1, GRS-2) and type 2 diabetes (GRS-T2D), were calculated. GRS-C1 and GRS-C2 were based on SNPs that have previously been shown to be associated with residual beta cell function. Regression models were used to investigate the association between GRS and residual beta cell function, assessed using the urinary C-peptide/creatinine ratio, and the association between GRS and continuous glucose monitor metrics. RESULTS Higher GRS-1 and higher GRS-2 both showed a significant association with undetectable UCPCR (OR 0.78; 95% CI 0.69, 0.89 and OR 0.84: 95% CI 0.75, 0.93, respectively), which were attenuated after correction for sex and age of onset (GRS-2) and disease duration (GRS-1). Higher GRS-C2 was associated with detectable urinary C-peptide/creatinine ratio (≥0.01 nmol/mmol) after correction for sex and age of onset (OR 6.95; 95% CI 1.19, 40.75). A higher GRS-T2D was associated with less time below range (TBR) (OR for TBR<4% 1.41; 95% CI 1.01 to 1.96) and lower glucose coefficient of variance (β -1.53; 95% CI -2.76, -0.29). CONCLUSIONS/INTERPRETATION Diabetes-related GRS are associated with residual beta cell function in individuals with type 1 diabetes. These findings suggest some genetic contribution to preservation of beta cell function.
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Affiliation(s)
- Coco M Fuhri Snethlage
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
| | - Manon Balvers
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Bart Ferwerda
- Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, Amsterdam, the Netherlands
| | - Elena Rampanelli
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Pleun de Groen
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Bart O Roep
- Leids Universitair Medisch Centrum, Internal Medicine, Leiden, the Netherlands
| | - Hilde Herrema
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Timothy J McDonald
- Peninsula College of Medicine and Dentistry, Peninsula NIHR Clinical Research Facility, Exeter, Devon, UK
| | - Daniël H van Raalte
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Department of Endocrinology and Metabolism, Amsterdam UMC, Amsterdam, the Netherlands
- Diabeter Center Amsterdam, Amsterdam, the Netherlands
| | - Michael N Weedon
- Peninsula College of Medicine and Dentistry, Peninsula NIHR Clinical Research Facility, Exeter, Devon, UK
| | - Richard A Oram
- Peninsula College of Medicine and Dentistry, Peninsula NIHR Clinical Research Facility, Exeter, Devon, UK
| | - Max Nieuwdorp
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Diabeter Center Amsterdam, Amsterdam, the Netherlands
| | - Nordin M J Hanssen
- Department of (Experimental) Vascular and Internal Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
- Diabeter Center Amsterdam, Amsterdam, the Netherlands
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7
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Robertson CC, Elgamal RM, Henry-Kanarek BA, Arvan P, Chen S, Dhawan S, Eizirik DL, Kaddis JS, Vahedi G, Parker SCJ, Gaulton KJ, Soleimanpour SA. Untangling the genetics of beta cell dysfunction and death in type 1 diabetes. Mol Metab 2024; 86:101973. [PMID: 38914291 PMCID: PMC11283044 DOI: 10.1016/j.molmet.2024.101973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 06/18/2024] [Accepted: 06/19/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) is a complex multi-system disease which arises from both environmental and genetic factors, resulting in the destruction of insulin-producing pancreatic beta cells. Over the past two decades, human genetic studies have provided new insight into the etiology of T1D, including an appreciation for the role of beta cells in their own demise. SCOPE OF REVIEW Here, we outline models supported by human genetic data for the role of beta cell dysfunction and death in T1D. We highlight the importance of strong evidence linking T1D genetic associations to bona fide candidate genes for mechanistic and therapeutic consideration. To guide rigorous interpretation of genetic associations, we describe molecular profiling approaches, genomic resources, and disease models that may be used to construct variant-to-gene links and to investigate candidate genes and their role in T1D. MAJOR CONCLUSIONS We profile advances in understanding the genetic causes of beta cell dysfunction and death at individual T1D risk loci. We discuss how genetic risk prediction models can be used to address disease heterogeneity. Further, we present areas where investment will be critical for the future use of genetics to address open questions in the development of new treatment and prevention strategies for T1D.
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Affiliation(s)
- Catherine C Robertson
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Center for Precision Health Research, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
| | - Ruth M Elgamal
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA
| | - Belle A Henry-Kanarek
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Peter Arvan
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, New York, NY, USA; Center for Genomic Health, Weill Cornell Medicine, New York, NY, USA
| | - Sangeeta Dhawan
- Department of Translational Research and Cellular Therapeutics, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope, Duarte, CA, USA
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - John S Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Golnaz Vahedi
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Stephen C J Parker
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
| | - Kyle J Gaulton
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
| | - Scott A Soleimanpour
- Department of Internal Medicine and Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA.
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Fuhri Snethlage CM, McDonald TJ, Oram RD, de Groen P, Rampanelli E, Schimmel AW, Holleman F, Siegelaar S, Hoekstra J, Brouwer CB, Knop FK, Verchere CB, van Raalte DH, Roep BO, Nieuwdorp M, Hanssen NM. Residual β-Cell Function Is Associated With Longer Time in Range in Individuals With Type 1 Diabetes. Diabetes Care 2024; 47:1114-1121. [PMID: 37535870 PMCID: PMC11208747 DOI: 10.2337/dc23-0776] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Accepted: 07/13/2023] [Indexed: 08/05/2023]
Abstract
OBJECTIVE Little is known about the influence of residual islet function on glycemic control in type 1 diabetes (T1D). We investigated the associations between residual β-cell function and metrics of continuous glucose monitoring (CGM) in individuals with T1D. RESEARCH DESIGN AND METHODS In this cross-sectional cohort comprising 489 individuals (64% female, age 41.0 ± 14.0 years), T1D duration was 15.0 (interquartile range [IQR] 6.0-29.0) years. Individuals had a time in range (TIR) of 66% (IQR 52-80%) and a urinary C-peptide-to-creatinine ratio (UCPCR) of 0.01 (IQR 0.00-0.41) nmol/mmol. To assess β-cell function, we measured UCPCR (detectable >0.01 nmol/mmol), and to assess α-cell function, fasting plasma glucagon/glucose ratios were measured. CGM was used to record TIR (3.9-10 mmol/L), time below range (TBR) (<3.9 mmol/L), time above range (TAR) (>10 mmol/L), and glucose coefficient of variance (CV). For CGM, 74.7% used FreeStyle Libre 2, 13.8% Medtronic Guardian, and 11.5% Dexcom G6 as their device. RESULTS The percentage of patients with T1D who had a detectable UCPCR was 49.4%. A higher UCPCR correlated with higher TIR (r = 0.330, P < 0.05), lower TBR (r = -0.237, P < 0.05), lower TAR (r = -0.302, P < 0.05), and lower glucose CV (r = -0.356, P < 0.05). A higher UCPCR correlated negatively with HbA1c levels (r = -0.183, P < 0.05) and total daily insulin dose (r = -0.183, P < 0.05). Glucagon/glucose ratios correlated with longer TIR (r = 0.234, P < 0.05). CONCLUSIONS Significantly longer TIR, shorter TBR and TAR, and lower CV were observed in individuals with greater UCPCR-assessed β-cell function. Therefore, better CGM-derived metrics in individuals with preserved β-cell function may be a contributor to a lower risk of developing long-term complications.
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Affiliation(s)
- Coco M. Fuhri Snethlage
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Timothy J. McDonald
- Peninsula College of Medicine and Dentistry, Peninsula National Institute for Health and Care Research Clinical Research Facility, Exeter, Devon, U.K
| | - Richard D. Oram
- Peninsula College of Medicine and Dentistry, Peninsula National Institute for Health and Care Research Clinical Research Facility, Exeter, Devon, U.K
| | - Pleun de Groen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Elena Rampanelli
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Alinda W.M. Schimmel
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Frits Holleman
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Sarah Siegelaar
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Joost Hoekstra
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | | | - Filip K. Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, Herlev, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - C. Bruce Verchere
- BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Daniël H. van Raalte
- Department of Endocrinology and Metabolism, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
| | - Bart O. Roep
- Internal Medicine, Leids Universitair Medisch Centrum, Leiden, the Netherlands
| | - Max Nieuwdorp
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Nordin M.J. Hanssen
- Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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Taylor GS, Smith K, Scragg J, McDonald TJ, Shaw JA, West DJ, Roberts LD. The metabolome as a diagnostic for maximal aerobic capacity during exercise in type 1 diabetes. Diabetologia 2024; 67:1413-1428. [PMID: 38662134 PMCID: PMC11153288 DOI: 10.1007/s00125-024-06153-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/07/2024] [Indexed: 04/26/2024]
Abstract
AIMS/HYPOTHESIS Our aim was to characterise the in-depth metabolic response to aerobic exercise and the impact of residual pancreatic beta cell function in type 1 diabetes. We also aimed to use the metabolome to distinguish individuals with type 1 diabetes with reduced maximal aerobic capacity in exercise defined byV ˙ O 2peak . METHODS Thirty participants with type 1 diabetes (≥3 years duration) and 30 control participants were recruited. Groups did not differ in age or sex. After quantification of peak stimulated C-peptide, participants were categorised into those with undetectable (<3 pmol/l), low (3-200 pmol/l) or high (>200 pmol/l) residual beta cell function. Maximal aerobic capacity was assessed byV ˙ O 2peak test and did not differ between control and type 1 diabetes groups. All participants completed 45 min of incline treadmill walking (60%V ˙ O 2peak ) with venous blood taken prior to exercise, immediately post exercise and after 60 min recovery. Serum was analysed using targeted metabolomics. Metabolomic data were analysed by multivariate statistics to define the metabolic phenotype of exercise in type 1 diabetes. Receiver operating characteristic (ROC) curves were used to identify circulating metabolomic markers of maximal aerobic capacity (V ˙ O 2peak ) during exercise in health and type 1 diabetes. RESULTS Maximal aerobic capacity (V ˙ O 2peak ) inversely correlated with HbA1c in the type 1 diabetes group (r2=0.17, p=0.024). Higher resting serum tricarboxylic acid cycle metabolites malic acid (fold change 1.4, p=0.001) and lactate (fold change 1.22, p=1.23×10-5) differentiated people with type 1 diabetes. Higher serum acylcarnitines (AC) (AC C14:1, F value=12.25, p=0.001345; AC C12, F value=11.055, p=0.0018) were unique to the metabolic response to exercise in people with type 1 diabetes. C-peptide status differentially affected metabolic responses in serum ACs during exercise (AC C18:1, leverage 0.066; squared prediction error 3.07). The malic acid/pyruvate ratio in rested serum was diagnostic for maximal aerobic capacity (V ˙ O 2peak ) in people with type 1 diabetes (ROC curve AUC 0.867 [95% CI 0.716, 0.956]). CONCLUSIONS/INTERPRETATION The serum metabolome distinguishes high and low maximal aerobic capacity and has diagnostic potential for facilitating personalised medicine approaches to manage aerobic exercise and fitness in type 1 diabetes.
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Affiliation(s)
- Guy S Taylor
- Human Nutrition & Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Kieran Smith
- Human Nutrition & Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
- The Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK
| | - Jadine Scragg
- Human Nutrition & Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | | | - James A Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Daniel J West
- Human Nutrition & Exercise Research Centre, Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, UK.
| | - Lee D Roberts
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK.
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10
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Melander SA, Larsen AT, Karsdal MA, Henriksen K. Are insulin sensitizers the new strategy to treat Type 1 diabetes? A long-acting dual amylin and calcitonin receptor agonist improves insulin-mediated glycaemic control and controls body weight. Br J Pharmacol 2024; 181:1829-1842. [PMID: 38378168 DOI: 10.1111/bph.16329] [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: 08/16/2023] [Revised: 12/19/2023] [Accepted: 01/08/2024] [Indexed: 02/22/2024] Open
Abstract
BACKGROUND AND PURPOSE Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D. EXPERIMENTAL APPROACH Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg-1) to induce T1D. Humulin (1 U/200 g·day-1 or 2 U/200 g·day-1) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg-1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study. KEY RESULTS Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation. CONCLUSION AND IMPLICATIONS The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits.
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Affiliation(s)
| | | | | | - Kim Henriksen
- Nordic Bioscience, Herlev, Denmark
- KeyBioscience AG, Stans, Switzerland
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11
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James EA, Joglekar AV, Linnemann AK, Russ HA, Kent SC. The beta cell-immune cell interface in type 1 diabetes (T1D). Mol Metab 2023; 78:101809. [PMID: 37734713 PMCID: PMC10622886 DOI: 10.1016/j.molmet.2023.101809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND T1D is an autoimmune disease in which pancreatic islets of Langerhans are infiltrated by immune cells resulting in the specific destruction of insulin-producing islet beta cells. Our understanding of the factors leading to islet infiltration and the interplay of the immune cells with target beta cells is incomplete, especially in human disease. While murine models of T1D have provided crucial information for both beta cell and autoimmune cell function, the translation of successful therapies in the murine model to human disease has been a challenge. SCOPE OF REVIEW Here, we discuss current state of the art and consider knowledge gaps concerning the interface of the islet beta cell with immune infiltrates, with a focus on T cells. We discuss pancreatic and immune cell phenotypes and their impact on cell function in health and disease, which we deem important to investigate further to attain a more comprehensive understanding of human T1D disease etiology. MAJOR CONCLUSIONS The last years have seen accelerated development of approaches that allow comprehensive study of human T1D. Critically, recent studies have contributed to our revised understanding that the pancreatic beta cell assumes an active role, rather than a passive position, during autoimmune disease progression. The T cell-beta cell interface is a critical axis that dictates beta cell fate and shapes autoimmune responses. This includes the state of the beta cell after processing internal and external cues (e.g., stress, inflammation, genetic risk) that that contributes to the breaking of tolerance by hyperexpression of human leukocyte antigen (HLA) class I with presentation of native and neoepitopes and secretion of chemotactic factors to attract immune cells. We anticipate that emerging insights about the molecular and cellular aspects of disease initiation and progression processes will catalyze the development of novel and innovative intervention points to provide additional therapies to individuals affected by T1D.
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Affiliation(s)
- Eddie A James
- Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Alok V Joglekar
- Center for Systems Immunology and Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Amelia K Linnemann
- Center for Diabetes and Metabolic Diseases, and Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Holger A Russ
- Diabetes Institute, University of Florida, Gainesville, FL, USA; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA
| | - Sally C Kent
- Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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12
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Caldara R, Tomajer V, Monti P, Sordi V, Citro A, Chimienti R, Gremizzi C, Catarinella D, Tentori S, Paloschi V, Melzi R, Mercalli A, Nano R, Magistretti P, Partelli S, Piemonti L. Allo Beta Cell transplantation: specific features, unanswered questions, and immunological challenge. Front Immunol 2023; 14:1323439. [PMID: 38077372 PMCID: PMC10701551 DOI: 10.3389/fimmu.2023.1323439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/06/2023] [Indexed: 12/18/2023] Open
Abstract
Type 1 diabetes (T1D) presents a persistent medical challenge, demanding innovative strategies for sustained glycemic control and enhanced patient well-being. Beta cells are specialized cells in the pancreas that produce insulin, a hormone that regulates blood sugar levels. When beta cells are damaged or destroyed, insulin production decreases, which leads to T1D. Allo Beta Cell Transplantation has emerged as a promising therapeutic avenue, with the goal of reinstating glucose regulation and insulin production in T1D patients. However, the path to success in this approach is fraught with complex immunological hurdles that demand rigorous exploration and resolution for enduring therapeutic efficacy. This exploration focuses on the distinct immunological characteristics inherent to Allo Beta Cell Transplantation. An understanding of these unique challenges is pivotal for the development of effective therapeutic interventions. The critical role of glucose regulation and insulin in immune activation is emphasized, with an emphasis on the intricate interplay between beta cells and immune cells. The transplantation site, particularly the liver, is examined in depth, highlighting its relevance in the context of complex immunological issues. Scrutiny extends to recipient and donor matching, including the utilization of multiple islet donors, while also considering the potential risk of autoimmune recurrence. Moreover, unanswered questions and persistent gaps in knowledge within the field are identified. These include the absence of robust evidence supporting immunosuppression treatments, the need for reliable methods to assess rejection and treatment protocols, the lack of validated biomarkers for monitoring beta cell loss, and the imperative need for improved beta cell imaging techniques. In addition, attention is drawn to emerging directions and transformative strategies in the field. This encompasses alternative immunosuppressive regimens and calcineurin-free immunoprotocols, as well as a reevaluation of induction therapy and recipient preconditioning methods. Innovative approaches targeting autoimmune recurrence, such as CAR Tregs and TCR Tregs, are explored, along with the potential of stem stealth cells, tissue engineering, and encapsulation to overcome the risk of graft rejection. In summary, this review provides a comprehensive overview of the inherent immunological obstacles associated with Allo Beta Cell Transplantation. It offers valuable insights into emerging strategies and directions that hold great promise for advancing the field and ultimately improving outcomes for individuals living with diabetes.
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Affiliation(s)
- Rossana Caldara
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valentina Tomajer
- Pancreatic Surgery, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Paolo Monti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valeria Sordi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Antonio Citro
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Raniero Chimienti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Chiara Gremizzi
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Davide Catarinella
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Stefano Tentori
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Vera Paloschi
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Raffella Melzi
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Alessia Mercalli
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Rita Nano
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Paola Magistretti
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Stefano Partelli
- Pancreatic Surgery, Pancreas Translational & Clinical Research Center, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- Clinic Unit of Regenerative Medicine and Organ Transplants, IRCCS Ospedale San Raffaele, Milan, Italy
- Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
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13
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Bhagadurshah RR, Eagappan S, Kasthuri Santharam R, Subbiah S. The Impact of Body Mass Index, Residual Beta Cell Function and Estimated Glucose Disposal Rate on the Development of Double Diabetes and Microvascular Complications in Patients With Type 1 Diabetes Mellitus. Cureus 2023; 15:e48979. [PMID: 38111445 PMCID: PMC10726016 DOI: 10.7759/cureus.48979] [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] [Accepted: 11/15/2023] [Indexed: 12/20/2023] Open
Abstract
Background The clinical impact of body mass index (BMI), residual beta cell function and estimated glucose disposal rate (eGDR) in the development of double diabetes (DD) and microvascular complications are largely unknown. We aimed to assess whether BMI, residual beta cell function measured by plasma "C" peptide and insulin resistance measured by eGDR have any impact on the development of DD and microvascular complications in patients with type 1 diabetes mellitus (T1DM). Methods It is a cross-sectional observational study involving 113 T1DM patients of more than five years duration who were classified into two groups: normal BMI (18.5-22.9 kg/m2) and overweight/obese group (≥ 23kg/m2) based on Asian BMI classification. Based on their eGDR values, they were grouped into four categories: ≥ 8, 6-7.99, 4-5.99, and < 4 mg/kg/min. The prevalence of DD based on eGDR values was determined. Their BMI and different eGDR categories were compared with the prevalence of diabetic retinopathy and nephropathy and their odds ratio (OR) was calculated. Results The median and interquartile range (IQR) of the eGDR of the overweight/obese group was significantly lower than the normal BMI group (5.3 [3.96-8.15] vs 8.72 [6.50-9.77 mg/kg/min], p < 0.001). The prevalence of DD in the overweight/obese T1DM group and normal BMI group was 75% and 33.3% respectively. The OR of retinopathy and nephropathy in the overweight/obese group was 3.28 (p = 0.007) and 3.01 (p = 0.015) respectively when compared to the normal BMI group. The OR of retinopathy and nephropathy in T1DM patients with eGDR < 4 mg/kg/min was 17.13 (p = 0.001) and 18.5 (p = 0.001) respectively. The lower the eGDR values, the higher the prevalence of retinopathy and nephropathy regardless of HbA1c levels. Conclusion As overweight and obesity are increasingly becoming more prevalent in T1DM, the eGDR will better predict the development of DD and microvascular complications irrespective of HbA1c levels. It is more useful as a variable and easily inducted into routine clinical practice. However, residual beta cell function was not useful in predicting the development of microvascular complications.
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Affiliation(s)
- Rameez Raja Bhagadurshah
- Department of Endocrinology and Diabetology, Madurai Medical College and Government Rajaji Hospital, Madurai, IND
| | - Subbiah Eagappan
- Department of Endocrinology and Diabetology, Madurai Medical College and Government Rajaji Hospital, Madurai, IND
| | - Raghavan Kasthuri Santharam
- Department of Endocrinology and Diabetology, Madurai Medical College and Government Rajaji Hospital, Madurai, IND
| | - Sridhar Subbiah
- Department of Endocrinology and Diabetology, Madurai Medical College and Government Rajaji Hospital, Madurai, IND
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14
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Thompson PJ, Pipella J, Rutter GA, Gaisano HY, Santamaria P. Islet autoimmunity in human type 1 diabetes: initiation and progression from the perspective of the beta cell. Diabetologia 2023; 66:1971-1982. [PMID: 37488322 PMCID: PMC10542715 DOI: 10.1007/s00125-023-05970-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 05/30/2023] [Indexed: 07/26/2023]
Abstract
Type 1 diabetes results from the poorly understood process of islet autoimmunity, which ultimately leads to the loss of functional pancreatic beta cells. Mounting evidence supports the notion that the activation and evolution of islet autoimmunity in genetically susceptible people is contingent upon early life exposures affecting the islets, especially beta cells. Here, we review some of the recent advances and studies that highlight the roles of these changes as well as antigen presentation and stress response pathways in beta cells in the onset and propagation of the autoimmune process in type 1 diabetes. Future progress in this area holds promise for advancing islet- and beta cell-directed therapies that could be implemented in the early stages of the disease and could be combined with immunotherapies.
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Affiliation(s)
- Peter J Thompson
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.
- Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, MB, Canada.
| | - Jasmine Pipella
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
- Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, MB, Canada
| | - Guy A Rutter
- CRCHUM and Department of Medicine, Université de Montréal, Montréal, QC, Canada.
- Department of Diabetes, Endocrinology and Medicine, Faculty of Medicine, Imperial College, London, UK.
- LKC School of Medicine, Nanyang Technological College, Singapore, Republic of Singapore.
| | - Herbert Y Gaisano
- Departments of Medicine and Physiology, University of Toronto, Toronto, ON, Canada
| | - Pere Santamaria
- Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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15
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Gabbay MAL, Crispim F, Dib SA. Residual β-cell function in Brazilian Type 1 diabetes after 3 years of diagnosis: prevalence and association with low presence of nephropathy. Diabetol Metab Syndr 2023; 15:51. [PMID: 36935525 PMCID: PMC10026390 DOI: 10.1186/s13098-023-01014-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 03/04/2023] [Indexed: 03/21/2023] Open
Abstract
BACKGROUND Persistence of β cell-function in Type 1 diabetes (T1D) is associated with glycaemia stability and lower prevalence of microvascular complications. We aimed to assess the prevalence of residual C- peptide secretion in long-term Brazilian childhood onset T1D receiving usual diabetes care and its association to clinical, metabolic variables and microvascular complications. METHODS A cross-sectional observational study with 138 T1D adults with ≥ 3 years from the diagnosis by routine diabetes care. Clinical, metabolic variables and microvascular complications were compared between positive ultra-sensitive fasting serum C-peptide (FCP +) and negative (FCP-) participants. RESULTS T1D studied had ≥ 3 yrs. of diagnosis and 60% had FCP > 1.15 pmol/L. FCP + T1D were older at diagnosis (10 vs 8 y.o; p = 0.03) and had less duration of diabetes (11 vs 15 y.o; p = 0.002). There was no association between the FCP + and other clinical and metabolic variable but there was inversely association with microalbuminuria (28.6% vs 13.4%, p = 0.03), regardless of HbA1c. FCP > 47 pmol/L were associated with nephropathy protection but were not related to others microvascular complications. CONCLUSION Residual insulin secretion is present in 60% of T1D with ≥ 3 years of diagnosis in routine diabetes care. FCP + was positively associated with age of diagnosis and negatively with duration of disease and microalbuminuria, regardless of HbA1c.
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Affiliation(s)
- Monica A L Gabbay
- Centre for Diabetes, Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
- Molecular Biology Laboratory, Endocrinology Division, Department of Medicine Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
| | - Felipe Crispim
- Molecular Biology Laboratory, Endocrinology Division, Department of Medicine Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Sergio A Dib
- Centre for Diabetes, Endocrinology Division, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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16
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Irilouzadian R, Afaghi S, Esmaeili Tarki F, Rahimi F, Malekpour Alamadari N. Urinary c-peptide creatinine ratio (UCPCR) as a predictor of coronary artery disease in type 1 diabetes mellitus. Endocrinol Diabetes Metab 2023; 6:e413. [PMID: 36808709 PMCID: PMC10164436 DOI: 10.1002/edm2.413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/28/2023] [Accepted: 02/05/2023] [Indexed: 02/23/2023] Open
Abstract
BACKGROUND Elevated C-peptide has been suggested as a risk factor for coronary artery disease (CAD). Elevated urinary C-peptide to creatinine ratio (UCPCR) as an alternative measurement is shown to be related to insulin secretion dysfunction; however, data regarding UCPCR predictive value for CAD in diabetes mellitus (DM) are scarce. Therefore, we aimed to assess the UCPCR association with CAD in type 1 DM (T1DM) patients. METHODS 279 patients previously diagnosed with T1DM included and categorized into two groups of CAD (n = 84) and without-CAD (n = 195). Furthermore, each group was divided into obese (body mass index (BMI) ≥ 30) and non-obese (BMI < 30) groups. Four models utilizing the binary logistic regression were designed to evaluate the role of UCPCR in CAD adjusted for well-known risk factors and mediators. RESULTS Median level of UCPCR was higher in CAD group compared to non-CAD group (0.07 vs. 0.04, respectively). Also, the well-acknowledged risk factors including being active smoker, hypertension, duration of diabetes, and body mass index (BMI) as well as higher levels of haemoglobin A1C (HbA1C), total cholesterol (TC), low-density lipoprotein (LDL) and estimated glomeruli filtration rate (e-GFR) had more significant pervasiveness in CAD patients. Based on multiple adjustments by logistic regression, UCPCR was a strong risk factor of CAD among T1DM patients independent of hypertension, demographic variables (gender, age, smoking, alcohol consumption), diabetes-related factors (diabetes duration, FBS, HbA1C), lipid profile (TC, LDL, HDL, TG) and renal-related indicators (creatinine, e-GFR, albuminuria, uric acid) in both patients with BMI≥30 and BMI < 30. CONCLUSION UCPCR is associated with clinical CAD, independent of CAD classic risk factors, glycaemic control, insulin resistance and BMI in type 1 DM patients.
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Affiliation(s)
- Rana Irilouzadian
- Burn Research Center, Iran university of medical sciences, Tehran, Iran
| | - Siamak Afaghi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farzad Esmaeili Tarki
- Research institute of internal medicine, Shahid Modarres hospital, Shahid Beheshti university of medical sciences, Tehran, Iran
| | - Fatemehsadat Rahimi
- Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nasser Malekpour Alamadari
- Department of Surgery, Clinical Research and Development Center, Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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17
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Jansen TJP, Brom M, Boss M, Buitinga M, Tack CJ, van Meijel LA, de Galan BE, Gotthardt M. Importance of beta cell mass for glycaemic control in people with type 1 diabetes. Diabetologia 2023; 66:367-375. [PMID: 36394644 PMCID: PMC9669532 DOI: 10.1007/s00125-022-05830-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 10/10/2022] [Indexed: 11/18/2022]
Abstract
AIMS/HYPOTHESIS The role of beta cell mass in the balance of glucose control and hypoglycaemic burden in people with type 1 diabetes is unclear. We applied positron emission tomography (PET) imaging with radiolabelled exendin to compare beta cell mass among people with type 1 diabetes and either low glucose variability (LGV) or high glucose variability (HGV). METHODS All participants with either LGV (n=9) or HGV (n=7) underwent a mixed-meal tolerance test to determine beta cell function and wore a blinded continuous glucose monitor for a week. After an i.v. injection with [68Ga]Ga-NODAGA-exendin-4, PET images were acquired for the quantification of pancreatic uptake of radiolabelled exendin. The mean standardised uptake value (SUVmean) of the pancreas was used to determine the amount of beta cell mass. RESULTS Participants with LGV had lower HbA1c (46.0 mmol/mol [44.5-52.5] [6.4% (6.3-7)] vs 80 mmol/mol [69.0-110] [9.5% (8.5-12.2)], p=0.001) and higher time in range (TIR) (75.6% [73.5-90.3] vs 38.7% [25.1-48.5], p=0.002) than those with HGV. The SUVmean of the pancreas was higher for the LGV than for the HGV group (5.1 [3.6-5.6] vs 2.9 [2.1-3.4], p=0.008). The AUCC-peptide:AUCglucose ratio was numerically, but not statistically, higher in the LGV compared with the HGV group (2.7×10-2 [6.2×10-4-5.3×10-2] vs 9.3×10-4 [4.7×10-4-5.2×10-3], p=0.21). SUVmean correlated with the AUCC-peptide:AUCglucose ratio (Pearson r=0.64, p=0.01), as well as with the TIR (r=0.64, p=0.01) and the SD of interstitial glucose levels (r=-0.66, p=0.007). CONCLUSION/INTERPRETATION Our data show higher beta cell mass in people with type 1 diabetes and LGV than in those with HGV, independent of beta cell function.
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Affiliation(s)
- Theodorus J P Jansen
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Maarten Brom
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Marti Boss
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Mijke Buitinga
- Nutrition and Movement Sciences, Maastricht University, Maastricht, the Netherlands
- Radiology and Nuclear Medicine, Maastricht UMC+, Maastricht, the Netherlands
| | - Cees J Tack
- Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Lian A van Meijel
- Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Internal Medicine, Maxima Medical Center, Veldhoven, the Netherlands
| | - Bastiaan E de Galan
- Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
- Internal Medicine, Maastricht UMC+, Maastricht, the Netherlands
- CARIM School for Cardiovascular Disease, Maastricht University, Maastricht, the Netherlands
| | - Martin Gotthardt
- Department of Medical Imaging, Radboud University Medical Center, Nijmegen, the Netherlands
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Kurpiewska E, Ciężki S, Jamiołkowska-Sztabkowska M, Polkowska A, Starosz A, Grubczak K, Moniuszko M, Bossowski A, Głowińska-Olszewska B. Excessive BMI is associated with higher C-peptide level at recognition but also with its greater loss in two years clinical observation in children with new onset type 1 diabetes. Front Immunol 2023; 14:1176403. [PMID: 37180128 PMCID: PMC10174309 DOI: 10.3389/fimmu.2023.1176403] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/17/2023] [Indexed: 05/15/2023] Open
Abstract
Introduction The prevalence of obesity in general pediatric population increases without sparing children with T1D. We intended to find factors associated with the possibility of preserving endogenous insulin secretion in individuals with long-standing T1D. At onset, higher BMI is associated with higher C-peptide level, which may indicate to be one of the favorable factors involved in preserving residual β-cell function. The study determines the influence of BMI on C-peptide secretion in children newly diagnosed with T1D in two years observation. Methods We assessed the possible relationship between selected pro- and anti-inflammatory cytokines, body mass at recognition and β-cell function status. 153 pediatric patients with newly diagnosed T1D were divided into quartiles according to BMI-SDS index. We separated a group consisted of patients with BMI-SDS >1. Participants were followed up for two years and examined for changes in body weight, HbA1c, and insulin requirement. C-peptide was assessed at baseline and after two years. We evaluated the patients' levels of selected inflammatory cytokines at baseline. Results Subjects with higher BMI-SDS presented higher serum C-peptide levels and lower insulin requirements at diagnosis than children with lower body weight. The two-year follow-up showed that C-peptide levels of obese patients dropped more rapidly than in children with BMI-SDS within normal limits. The group with BMI-SDS >1 showed the greatest decrease in C-peptide level. Despite statistically insignificant differences in HbA1c at diagnosis between the study groups, in the fourth quartile and BMI-SDS >1 groups, HbA1c as well as insulin requirements increased after two years. The levels of cytokines varied the most between BMI-SDS <1 and BMI-SDS >1 groups and were significantly higher within BMI-SDS >1 group. Discussion Higher BMI, associated with enhanced levels of inflammatory cytokines, relates to preservation of C-peptide at T1D recognition in children but is not beneficial in the long term. A decrease in C-peptide levels combined with an increase in insulin requirements and in HbA1c among patients with high BMI occur, which may indicate a negative effect of excessive body weight on the long term preservation of residual β-cell function. The process seems to be mediated by inflammatory cytokines.
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Affiliation(s)
- Emilia Kurpiewska
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
| | - Sebastian Ciężki
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
| | - Milena Jamiołkowska-Sztabkowska
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
| | - Agnieszka Polkowska
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
| | - Aleksandra Starosz
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Białystok, Poland
| | - Kamil Grubczak
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Białystok, Poland
| | - Marcin Moniuszko
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, Białystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Bialystok, Białystok, Poland
| | - Artur Bossowski
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
| | - Barbara Głowińska-Olszewska
- Department of Pediatrics, Endocrinology, and Diabetology with Cardiology Division, Medical University of Bialystok, Białystok, Poland
- *Correspondence: Barbara Głowińska-Olszewska,
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Baxter F, Baillie N, Forbes S. Study protocol: a randomised controlled proof-of-concept real-world study - does maximising time in range using hybrid closed loop insulin delivery and a low carbohydrate diet restore the glucagon response to hypoglycaemia in adults with type 1 diabetes? BMJ Open 2022; 12:e054958. [PMID: 36600427 PMCID: PMC9772676 DOI: 10.1136/bmjopen-2021-054958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
INTRODUCTION People with type 1 diabetes (T1D) develop an impaired glucagon response to hypoglycaemia within 5 years of diagnosis, increasing their risk of severe hypoglycaemia. It is not known whether eliminating hypoglycaemia and hyperglycaemia allows recovery of this glucagon response. Hybrid closed loop (HCL) technologies improve glycaemic time in range (TIR). However, post-prandial glycaemic excursions are still evident. Consuming a low carbohydrate diet (LCD) may minimise these excursions. METHODS AND ANALYSIS This feasibility study will assess if maximising TIR (glucose ≥3.9 mmol/L≤10 mmol/L) using HCL systems plus an LCD (defined here as <130 g carbohydrate/day) for >8 months, restores the glucagon response to insulin-induced hypoglycaemia. Adults (n=24) with T1D (C-peptide <200 pmol/L), naïve to continuous glucose monitoring (CGM) and HCL systems, will be recruited and randomised to: group 1 (non-HCL) to continue their standard diabetes care with intermittent blinded CGM; or group 2 (HCL-LCD) to use the HCL system and follow a LCD. Baseline data on diet and glycaemia will be collected from all participants. The HCL-LCD group will then enter a 2-week run-in to acclimatise to their devices. Throughout, the HCL-LCD group will have their glucose closely monitored and adjusted aiming for glycaemic TIR >70%. Participants will have their glucagon response to hypoglycaemia measured at the beginning and 8 months later at the study end using a stepped hyperinsulinaemic hypoglycaemic clamp, in combination with the stable isotopes 6,6-2H2-glucose (D2-glucose) and 1,1,2,3,3-2H5-glycerol (D5-glycerol) to assess glucose and glycerol kinetics. The impact of hypoglycaemia on symptoms and cognitive function will be assessed during each clamp study. The primary outcome is the difference in the glucagon response to hypoglycaemia between and within groups at baseline versus study end. ETHICS AND DISSEMINATION Ethical (20/SS/0117)/institutional review board (2021/0001) approval has been obtained. The study will be disseminated by peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER NCT04614168.
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Affiliation(s)
- Faye Baxter
- University of Edinburgh Division of BHF Centre for Cardiovascular Science, Edinburgh, UK
- Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Nicola Baillie
- University of Edinburgh Division of BHF Centre for Cardiovascular Science, Edinburgh, UK
- Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Shareen Forbes
- University of Edinburgh Division of BHF Centre for Cardiovascular Science, Edinburgh, UK
- Department of Diabetes, Royal Infirmary of Edinburgh, Edinburgh, UK
- Edmonton Islet Transplant Programme, University of Alberta, Edmonton, Alberta, Canada
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20
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Eason RJ, Thomas NJ, Hill AV, Knight BA, Carr A, Hattersley AT, McDonald TJ, Shields BM, Jones AG. Routine Islet Autoantibody Testing in Clinically Diagnosed Adult-Onset Type 1 Diabetes Can Help Identify Misclassification and the Possibility of Successful Insulin Cessation. Diabetes Care 2022; 45:2844-2851. [PMID: 36205650 DOI: 10.2337/dc22-0623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 08/23/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Recent joint American Diabetes Association and European Association for the Study of Diabetes guidelines recommend routine islet autoantibody testing in all adults newly diagnosed with type 1 diabetes. We aimed to assess the impact of routine islet autoantibody testing in this population. RESEARCH DESIGN AND METHODS We prospectively assessed the relationship between islet autoantibody status (GADA, IA-2A, and ZNT8A), clinical and genetic characteristics, and progression (annual change in urine C-peptide-to-creatinine ratio [UCPCR]) in 722 adults (≥18 years old at diagnosis) with clinically diagnosed type 1 diabetes and diabetes duration <12 months. We also evaluated changes in treatment and glycemia over 2 years after informing participants and their clinicians of autoantibody results. RESULTS Of 722 participants diagnosed with type 1 diabetes, 24.8% (179) were autoantibody negative. This group had genetic and C-peptide characteristics suggestive of a high prevalence of nonautoimmune diabetes: lower mean type 1 diabetes genetic risk score (islet autoantibody negative vs. positive: 10.85 vs. 13.09 [P < 0.001] [type 2 diabetes 10.12]) and lower annual change in C-peptide (UCPCR), -24% vs. -43% (P < 0.001).After median 24 months of follow-up, treatment change occurred in 36.6% (60 of 164) of autoantibody-negative participants: 22.6% (37 of 164) discontinued insulin, with HbA1c similar to that of participants continuing insulin (57.5 vs. 60.8 mmol/mol [7.4 vs. 7.7%], P = 0.4), and 14.0% (23 of 164) added adjuvant agents to insulin. CONCLUSIONS In adult-onset clinically diagnosed type 1 diabetes, negative islet autoantibodies should prompt careful consideration of other diabetes subtypes. When routinely measured, negative antibodies are associated with successful insulin cessation. These findings support recent recommendations for routine islet autoantibody assessment in adult-onset type 1 diabetes.
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Affiliation(s)
- Russell J Eason
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | - Nicholas J Thomas
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | - Anita V Hill
- Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | - Bridget A Knight
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | - Alice Carr
- University of Exeter College of Medicine & Health, Exeter, U.K
| | - Andrew T Hattersley
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | - Timothy J McDonald
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
| | | | - Angus G Jones
- University of Exeter College of Medicine & Health, Exeter, U.K.,Royal Devon University Healthcare NHS Foundation Trust, Exeter, U.K
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21
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Carroll KR, Katz JD. Restoring tolerance to β-cells in Type 1 diabetes: Current and emerging strategies. Cell Immunol 2022; 380:104593. [PMID: 36081179 DOI: 10.1016/j.cellimm.2022.104593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 11/03/2022]
Abstract
Type 1 diabetes (T1D) results from insulin insufficiency due to islet death and dysfunction following T cell-mediated autoimmune attack. The technical feasibility of durable, functional autologous islet restoration is progressing such that it presents the most likely long-term cure for T1D but cannot succeed without the necessary counterpart of clinically effective therapeutic strategies that prevent grafted islets' destruction by pre-existing anti-islet T cells. While advances have been made in broad immunosuppression to lower off-target effects, the risk of opportunistic infections and cancers remains a concern, especially for well-managed T1D patients. Current immunomodulatory strategies in development focus on autologous Treg expansion, treatments to decrease antigen presentation and T effector (Teff) activation, and broad depletion of T cells with or without hematopoietic stem cell transplants. Emerging strategies harnessing the intensified DNA damage response present in expanding T cells, exacerbating their already high sensitivity to apoptosis to abate autoreactive Teff cells.
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Affiliation(s)
- Kaitlin R Carroll
- Center for Autoimmune, Musculoskeletal and Hematopoietic Diseases, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030, United States
| | - Jonathan D Katz
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, United States.
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22
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Carr AL, Inshaw JR, Flaxman CS, Leete P, Wyatt RC, Russell LA, Palmer M, Prasolov D, Worthington T, Hull B, Wicker LS, Dunger DB, Oram RA, Morgan NG, Todd JA, Richardson SJ, Besser RE. Circulating C-Peptide Levels in Living Children and Young People and Pancreatic β-Cell Loss in Pancreas Donors Across Type 1 Diabetes Disease Duration. Diabetes 2022; 71:1591-1596. [PMID: 35499624 PMCID: PMC9233242 DOI: 10.2337/db22-0097] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/16/2022] [Indexed: 11/13/2022]
Abstract
C-peptide declines in type 1 diabetes, although many long-duration patients retain low, but detectable levels. Histological analyses confirm that β-cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in the UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N = 4,079), with β-cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N = 235), stratified by recently reported age at diagnosis endotypes (<7, 7-12, ≥13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (<1-year duration: age <7 years: 18 of 20 [90%], 7-12 years: 107 of 110 [97%], ≥13 years: 58 of 61 [95%] vs. 1-5 years postdiagnosis: <7 years: 172 of 522 [33%], 7-12 years: 604 of 995 [61%], ≥13 years: 225 of 289 [78%]). A similar profile was observed in β-cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) β-cells <1 year postdiagnosis: age <7 years: 23 of 26 (88%), 7-12 years: 32 of 33 (97%), ≥13 years: 22 of 25 (88%) vs. 1-5 years postdiagnosis: <7 years: 1 of 12 (8.3%), 7-12 years: 7 of 13 (54%), ≥13 years: 7 of 8 (88%). These data should be considered in the planning and interpretation of intervention trials designed to promote β-cell retention and function.
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Affiliation(s)
- Alice L.J. Carr
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
- Corresponding authors: Alice Carr, , Rachel Besser, , or Sarah Richardson,
| | - Jamie R.J. Inshaw
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K
| | - Christine S. Flaxman
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Pia Leete
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Rebecca C. Wyatt
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Lydia A. Russell
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Matthew Palmer
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Dmytro Prasolov
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Thomas Worthington
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Bethany Hull
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Linda S. Wicker
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K
| | - David B. Dunger
- Department of Paediatrics, Addenbrooke's Hospital, University of Cambridge, Cambridge, U.K
| | - Richard A. Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Noel G. Morgan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - John A. Todd
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K
- National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K
| | - Sarah J. Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
- Corresponding authors: Alice Carr, , Rachel Besser, , or Sarah Richardson,
| | - Rachel E.J. Besser
- JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, U.K
- National Institute of Health Research (NIHR) Oxford Biomedical Research Centre, John Radcliffe Hospital, Oxford, U.K
- Corresponding authors: Alice Carr, , Rachel Besser, , or Sarah Richardson,
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23
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Pappachan JM, Sunil B, Fernandez CJ, Lahart IM, Ashraf AP. Diagnostic Test Accuracy of Urine C-peptide Creatinine Ratio for the Correct Identification of the Type of Diabetes: A Systematic Review. TOUCHREVIEWS IN ENDOCRINOLOGY 2022; 18:2-9. [PMID: 35949364 PMCID: PMC9354948 DOI: 10.17925/ee.2022.18.1.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 03/09/2022] [Indexed: 02/05/2023]
Abstract
Objective: To examine the accuracy of urine c-peptide creatinine ratio (UCPCR) for identifying the type of diabetes in appropriate clinical settings. Design: Systematic review of test accuracy studies on patients with different forms of diabetes. Data sources: Medline, Embase and Cochrane library databases from 1 January 2000 to 15 November 2020. Eligibility criteria: Studies reporting the use of UCPCR for diagnosing patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and monogenic forms of diabetes (categorized as maturity-onset diabetes of the young [MODY]). Study selection and data synthesis: Two reviewers independently assessed articles for inclusion and assessed the methodological quality of the studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, with input from a third reviewer to reach consensus when there was a dispute. Meta-analysis was performed with the studies reporting complete data to derive the pooled sensitivity, specificity and diagnostic odds ratio (DOR), and narrative synthesis only for those with incomplete data. Results: Nine studies with 4,488 patients were included in the qualitative synthesis, while only four of these (915 patients) had complete data and were included in the quantitative synthesis. All the studies had moderate risk of bias and applicability concerns. Meta-analysis of three studies (n=130) revealed sensitivity, specificity and DOR of 84.4% (95% confidence interval [CI] 68.1-93.2%), 91.6% (82.8-96.1%) and 59.9 (32.8-106.0), respectively, for diagnosing T1DM using a UCPCR cut-off of <0.2 nmol/mmol. For participants with T2DM (three studies; n=739), UCPCR >0.2 nmol/mmol was associated with sensitivity, specificity and DOR of 92.8% (84.2-96.9%), 81.6% (61.3-92.5%) and 56.9 (31.3-103.5), respectively. For patients with MODY in the appropriate clinical setting, a UCPCR cut-off of >0.2 nmol/mmol showed sensitivity, specificity and DOR of 85.2% (73.1-92.4%), 98.0% (92.4-99.5%) and 281.8 (57.5-1,379.7), respectively. Conclusions: Based on studies with moderate risk of bias and applicability concerns, UCPCR confers moderate to high sensitivity, specificity, and DOR for correctly identifying T1DM, T2DM and monogenic diabetes in appropriate clinical settings. Large multinational studies with multi-ethnic participation among different age groups are necessary before this test can be routinely used in clinical practice. Study registration: Protocol was registered as PROSPERO CRD42017060633.
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Affiliation(s)
- Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston, UK
- Faculty of Science, Manchester Metropolitan University, Manchester, UK
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Bhuvana Sunil
- Division of Pediatric Endocrinology & Diabetes, Mary Bridge Children's Hospital, Tacoma, WA, USA
| | | | - Ian M Lahart
- Faculty of Education, Health and Wellbeing, University of Wolverhampton, Walsall, UK
| | - Ambika P Ashraf
- Division of Pediatric Endocrinology & Diabetes, University of Alabama at Birmingham, AL USA
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24
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Nwosu BU. Partial Clinical Remission of Type 1 Diabetes: The Need for an Integrated Functional Definition Based on Insulin-Dose Adjusted A1c and Insulin Sensitivity Score. Front Endocrinol (Lausanne) 2022; 13:884219. [PMID: 35592786 PMCID: PMC9110823 DOI: 10.3389/fendo.2022.884219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 03/23/2022] [Indexed: 11/29/2022] Open
Abstract
Despite advances in the characterization of partial clinical remission (PR) of type 1 diabetes, an accurate definition of PR remains problematic. Two recent studies in children with new-onset T1D demonstrated serious limitations of the present gold standard definition of PR, a stimulated C-peptide (SCP) concentration of >300 pmol/L. The first study employed the concept of insulin sensitivity score (ISS) to show that 55% of subjects with new-onset T1D and a detectable SCP level of >300 pmol/L had low insulin sensitivity (IS) and thus might not be in remission when assessed by insulin-dose adjusted A1c (IDAA1c), an acceptable clinical marker of PR. The second study, a randomized controlled trial of vitamin D (ergocalciferol) administration in children and adolescents with new-onset T1D, demonstrated no significant difference in SCP between the ergocalciferol and placebo groups, but showed a significant blunting of the temporal trend in both A1c and IDAA1c in the ergocalciferol group. These two recent studies indicate the poor specificity and sensitivity of SCP to adequately characterize PR and thus call for a re-examination of current approaches to the definition of PR. They demonstrate the limited sensitivity of SCP, a static biochemical test, to detect the complex physiological changes that occur during PR such as changes in insulin sensitivity, insulin requirements, body weight, and physical activity. These shortcomings call for a broader definition of PR using a combination of functional markers such as IDAA1c and ISS to provide a valid assessment of PR that reaches beyond the static changes in SCP alone.
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Affiliation(s)
- Benjamin Udoka Nwosu
- Division of Endocrinology, Department of Pediatrics, Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, NY, United States
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25
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Taylor GS, Shaw AC, Smith K, Wason J, McDonald TJ, Oram RA, Stevenson E, Shaw JAM, West DJ. Capturing the real-world benefit of residual β-cell function during clinically important time-periods in established Type 1 diabetes. Diabet Med 2022; 39:e14814. [PMID: 35181926 PMCID: PMC9311680 DOI: 10.1111/dme.14814] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/18/2022] [Accepted: 02/16/2022] [Indexed: 11/26/2022]
Abstract
AIMS Many individuals with type 1 diabetes retain residual β-cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β-cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes. METHODS Under free-living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C-peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpepund ), low (Cpeplow : 0.001-0.19 nmol/mmol) and high (Cpephigh : ≥0.2 nmol/mmol). RESULTS Greater β-cell function was associated with incremental improvements in glycaemia. Cpephigh spent significantly greater time in normoglycaemia than Cpepund overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0-300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpepund had increased hyperglycaemia versus Cpeplow overnight and increased postprandial hypoglycaemic events compared with Cpephigh . For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner. CONCLUSIONS Residual β-cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial.
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Affiliation(s)
- Guy S. Taylor
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - Andy C. Shaw
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - Kieran Smith
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - James Wason
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - Timothy J. McDonald
- National Institute for Health ResearchExeter Clinical Research FacilityUniversity of Exeter Medical SchoolExeterUK
- Royal Devon and Exeter NHS Foundation TrustExeterUK
| | - Richard A. Oram
- National Institute for Health ResearchExeter Clinical Research FacilityUniversity of Exeter Medical SchoolExeterUK
- Royal Devon and Exeter NHS Foundation TrustExeterUK
| | - Emma Stevenson
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
| | - James A. M. Shaw
- Translational and Clinical Research InstituteNewcastle UniversityNewcastle upon TyneUK
- Newcastle Centre for Diabetes CareNewcastle upon Tyne Hospitals NHS Foundation TrustNewcastle upon TyneUK
| | - Daniel J. West
- Faculty of Medical SciencePopulation Health Sciences InstituteNewcastle UniversityNewcastle upon TyneUK
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Mitsui Y, Kuroda A, Ishizu M, Mori H, Kurahashi K, Kondo T, Yoshida S, Akehi Y, Aihara K, Endo I, Abe M, Matsuhisa M. Basal insulin requirement in patients with type 1 diabetes depends on the age and body mass index. J Diabetes Investig 2022; 13:292-298. [PMID: 33740836 PMCID: PMC8847154 DOI: 10.1111/jdi.13547] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/11/2021] [Accepted: 03/10/2021] [Indexed: 12/31/2022] Open
Abstract
AIMS/INTRODUCTION To investigate the basal insulin requirement in patients with type 1 diabetes who are on multiple daily injections (MDI) and to assess the patient characteristics that affect the percent of total daily basal insulin dose to the total daily insulin dose (%TBD/TDD). MATERIALS AND METHODS The subjects of this study were 67 inpatients with type 1 diabetes who were served diabetic meals of 25-30 kcal/kg standard body weight during several weeks of hospitalization. The basal insulin requirement was adjusted to keep the blood glucose level from bedtime to before breakfast within a 30 mg/dL difference. The bolus insulin dose before the meal was adjusted to keep the blood glucose level below 140 and 200 mg/dL before and 2 h after each meal, respectively. The total daily insulin dose (TDD), the percent of total daily basal insulin dose (TBD) to TDD (%TBD/TDD), and clinical characteristics were collected. RESULTS The median (Q1, Q3) of TDD was 33.0 (26.0, 49.0) units, and the %TBD/TDD was 24.1 ± 9.8%. The %TBD/TDD was positively correlated with the body mass index (BMI) and negatively correlated with the age at the onset and at the examination according to a univariate analysis. However, the %TBD/TDD was dependent on the BMI (β = 0.340, P = 0.004) and the age at examination (β = -0.288, P = 0.012) according to the multiple regression analysis. CONCLUSIONS The average %TBD/TDD in patients with type 1 diabetes on MDI was approximately 24% under inpatient conditions. The basal insulin requirement was dependent on the BMI and the age at examination.
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Affiliation(s)
- Yukari Mitsui
- Department of Hematology, Endocrinology and Metabolism Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Akio Kuroda
- Diabetes Therapeutics and Research CenterTokushima UniversityTokushimaJapan
| | - Masashi Ishizu
- Diabetes Therapeutics and Research CenterTokushima UniversityTokushimaJapan
| | - Hiroyasu Mori
- Diabetes Therapeutics and Research CenterTokushima UniversityTokushimaJapan
| | - Kiyoe Kurahashi
- Department of Hematology, Endocrinology and Metabolism Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Takeshi Kondo
- Department of Endocrinology and MetabolismTokushima Red Cross HospitalKomatsushimaJapan
| | - Sumiko Yoshida
- Department of Hematology, Endocrinology and Metabolism Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Yuko Akehi
- Diabetes Therapeutics and Research CenterTokushima UniversityTokushimaJapan
| | - Ken‐ichi Aihara
- Department of Community Medicine and Medical ScienceTokushima University Graduate School of Biomedical SciencesTokushimaJapan
| | - Itsuro Endo
- Department of Bioregulatory SciencesTokushima University Graduate School of Medical SciencesTokushimaJapan
| | - Masahiro Abe
- Department of Hematology, Endocrinology and Metabolism Institute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research CenterTokushima UniversityTokushimaJapan
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Taylor GS, Shaw A, Scragg JH, Smith K, Campbell MD, McDonald TJ, Shaw JA, Ross MD, West DJ. Type 1 Diabetes Patients With Different Residual Beta-Cell Function but Similar Age, HBA1c, and Cardiorespiratory Fitness Have Differing Exercise-Induced Angiogenic Cell Mobilisation. Front Endocrinol (Lausanne) 2022; 13:797438. [PMID: 35222269 PMCID: PMC8874313 DOI: 10.3389/fendo.2022.797438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/10/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Many individuals with type 1 diabetes retain residual beta-cell function. Sustained endogenous insulin and C-peptide secretion is associated with reduced diabetes related complications, but underlying mechanisms remain unclear. Lower circulating numbers of endothelial and hematopoietic progenitor cells (EPCs and HPCs), and the inability to increase the count of these cells in response to exercise, are also associated with increased diabetes complications and cardiovascular disease. It is unknown whether residual beta-cell function influences HPCs and EPCs. Thus, this study examined the influence of residual beta-cell function in type 1 diabetes upon exercise-induced changes in haematopoietic (HPCs) and endothelial progenitor cells (EPCs). METHODS Participants with undetectable stimulated C-peptide (n=11; Cpepund), 10 high C-peptide (Cpephigh; >200 pmol/L), and 11 non-diabetes controls took part in this observational exercise study, completing 45 minutes of intensive walking at 60% V˙O2peak . Clinically significant HPCs (CD34+) and EPCs (CD34+VEGFR2+) phenotypes for predicting future adverse cardiovascular outcomes, and subsequent cell surface expression of chemokine receptor 4 (CXCR4) and 7 (CXCR7), were enumerated at rest and immediately post-exercise by flow cytometry. RESULTS Exercise increased HPCs and EPCs phenotypes similarly in the Cpephigh and control groups (+34-121% across phenotypes, p<0.04); but Cpepund group did not significantly increase from rest, even after controlling for diabetes duration. Strikingly, the post-exercise Cpepund counts were still lower than Cpephigh at rest. CONCLUSIONS Residual beta-cell function is associated with an intact exercise-induced HPCs and EPCs mobilisation. As key characteristics (age, fitness, HbA1c) were similar between groups, the mechanisms underpinning the absent mobilisation within those with negative C-peptide, and the vascular implications, require further investigation.
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Affiliation(s)
- Guy S. Taylor
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Daniel J. West, ; Guy S. Taylor,
| | - Andy Shaw
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jadine H. Scragg
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
| | - Kieran Smith
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Matthew D. Campbell
- Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland, United Kingdom
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom
| | - Timothy J. McDonald
- National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom
- Academic Department of Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
| | - James A. Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- Newcastle Centre for Diabetes Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Mark D. Ross
- School of Applied Sciences, Edinburgh Napier University, Edinburgh, United Kingdom
| | - Daniel J. West
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Daniel J. West, ; Guy S. Taylor,
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Gauthier BR, Cobo-Vuilleumier N, López-Noriega L. Roles of extracellular vesicles associated non-coding RNAs in Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:1057407. [PMID: 36619588 PMCID: PMC9814720 DOI: 10.3389/fendo.2022.1057407] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022] Open
Abstract
Extracellular vesicles (EVs), especially exosomes (50 to 150 nm), have been shown to play important roles in a wide range of physiological and pathological processes, including metabolic diseases such as Diabetes Mellitus (DM). In the last decade, several studies have demonstrated how EVs are involved in cell-to-cell communication. EVs are enriched in proteins, mRNAs and non-coding RNAs (miRNAs, long non-coding RNAs and circRNAS, among others) which are transferred to recipient cells and may have a profound impact in either their survival or functionality. Several studies have pointed out the contribution of exosomal miRNAs, such as miR-l42-3p and miR-26, in the development of Type 1 and Type 2 DM (T1DM and T2DM), respectively. In addition, some miRNA families such as miR-let7 and miR-29 found in exosomes have been associated with both types of diabetes, suggesting that they share common etiological features. The knowledge about the role of exosomal long non-coding RNAs in this group of diseases is more immature, but the exosomal lncRNA MALAT1 has been found to be elevated in the plasma of individuals with T2DM, while more than 169 lncRNAs were reported to be differentially expressed between healthy donors and people with T1DM. Here, we review the current knowledge about exosomal non-coding RNAs in DM and discuss their potential as novel biomarkers and possible therapeutic targets.
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Affiliation(s)
- Benoit R. Gauthier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
- Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM), Madrid, Spain
- *Correspondence: Benoit R. Gauthier, ; Livia López-Noriega,
| | - Nadia Cobo-Vuilleumier
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
| | - Livia López-Noriega
- Andalusian Center for Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-Consejo Superior de Investigaciones Científicas (CSIC), Seville, Spain
- *Correspondence: Benoit R. Gauthier, ; Livia López-Noriega,
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29
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Wilhelm-Benartzi CS, Miller SE, Bruggraber S, Picton D, Wilson M, Gatley K, Chhabra A, Marcovecchio ML, Hendriks AEJ, Morobé H, Chmura PJ, Bond S, Aschemeier-Fuchs B, Knip M, Tree T, Overbergh L, Pall J, Arnaud O, Haller MJ, Nitsche A, Schulte AM, Mathieu C, Mander A, Dunger D. Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes. BMJ Open 2021; 11:e053669. [PMID: 34876434 PMCID: PMC8655536 DOI: 10.1136/bmjopen-2021-053669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION Type 1 diabetes (T1D) is a chronic autoimmune disease, characterised by progressive destruction of the insulin-producing β cells of the pancreas. One immunosuppressive agent that has recently shown promise in the treatment of new-onset T1D subjects aged 12-45 years is antithymocyte globulin (ATG), Thymoglobuline, encouraging further exploration in lower age groups. METHODS AND ANALYSIS Minimal effective low dose (MELD)-ATG is a phase 2, multicentre, randomised, double-blind, placebo-controlled, multiarm parallel-group trial in participants 5-25 years diagnosed with T1D within 3-9 weeks of planned treatment day 1. A total of 114 participants will be recruited sequentially into seven different cohorts with the first cohort of 30 participants being randomised to placebo, 2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg ATG total dose in a 1:1:1:1:1 allocation ratio. The next six cohorts of 12-15 participants will be randomised to placebo, 2.5 mg/kg, and one or two selected middle ATG total doses in a 1:1:1:1 or 1:1:1 allocation ratio, as dependent on the number of middle doses, given intravenously over two consecutive days. The primary objective will be to determine the changes in stimulated C-peptide response over the first 2 hours of a mixed meal tolerance test at 12 months for 2.5 mg/kg ATG arm vs the placebo. Conditional on finding a significant difference at 2.5 mg/kg, a minimally effective dose will be sought. Secondary objectives include the determination of the effects of a particular ATG treatment dose on (1) stimulated C-peptide, (2) glycated haemoglobin, (3) daily insulin dose, (4) time in range by intermittent continuous glucose monitoring measures, (5) fasting and stimulated dry blood spot (DBS) C-peptide measurements. ETHICS AND DISSEMINATION MELD-ATG received first regulatory and ethical approvals in Belgium in September 2020 and from the German and UK regulators as of February 2021. The publication policy is set in the INNODIA (An innovative approach towards understanding and arresting Type 1 diabetes consortium) grant agreement (www.innodia.eu). TRIAL REGISTRATION NUMBER NCT03936634; Pre-results.
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Affiliation(s)
| | - Sarah E Miller
- Department of Paediatrics, University of Cambridge, Cambridge, UK
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Diane Picton
- Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Mark Wilson
- Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Katrina Gatley
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Anita Chhabra
- Pharmacy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | | | - Hilde Morobé
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Piotr Jaroslaw Chmura
- Center for Protein Research, Kobenhavns Universitet Sundhedsvidenskabelige Fakultet, Kobenhavn, Denmark
| | - Simon Bond
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Bärbel Aschemeier-Fuchs
- Diabetes Centre for Children and Adolescents, Children's Hospital Auf der Bult, Hannover, Germany
| | - Mikael Knip
- Research Program for Clinical and Molecular Metabolism, University of Helsinki Faculty of Medicine, Helsinki, Finland
- Pediatric Research Centre, University of Helsinki Children's Hospital, Helsinki, Finland
| | - Timothy Tree
- Department of Immunobiology, King's College London, London, UK
| | - Lut Overbergh
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Jaivier Pall
- INNODIA Patient Advisory Committee, Madrid, Spain
| | | | - Michael J Haller
- Department of Pediatrics, University of Florida, Gainesville, Florida, USA
| | | | | | - Chantal Mathieu
- Katholieke Universiteit Leuven/ Universitaire Ziekenhuizen, Leuven, Belgium
| | - Adrian Mander
- Centre for Trials Research, College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK
| | - David Dunger
- Department of Paediatrics, University of Cambridge, Cambridge, UK
- Wellcome Trust-MRC Institute of Metabolic Science, Cambridge University, Cambridge, UK
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30
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Shi M, Xie Y, Tang R, Zhong T, Zhou Z, Li X. Three-phasic pattern of C-peptide decline in type 1 diabetes patients with partial remission. Diabetes Metab Res Rev 2021; 37:e3461. [PMID: 33928751 DOI: 10.1002/dmrr.3461] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 03/15/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022]
Abstract
AIMS To explore the different patterns of C-peptide decline in patients with and without partial remission of newly diagnosed type 1 diabetes (T1D). MATERIALS AND METHODS A total of 298 patients with new-onset T1D were followed up regularly at 3 months' interval to investigate the loss of C-peptide. Partial remission was determined by postprandial C-peptide ≥300 pmol/L or insulin dose-adjusted A1c ≤ 9 in the absence of C-peptide. Beta-cell function was defined as preserved, residual or failed by postprandial C-peptide of ≥200 pmol/L, 50-200 pmol/L or ≤50 pmol/L, respectively. RESULTS Altogether, 199 out of 298 patients (125 adults) had partial remission. The pattern of C-peptide change in patients with partial remission was three-phasic, demonstrating an upward trend followed by a downward trend of fast first and then slow, while the pattern in patients without partial remission was biphasic, showing an initial fast fall and a subsequent slower decrease. The patterns remained consistent when patients were stratified by the age of onset. At 3 years, there were 71% of the patients with partial remission still had preserved or residual beta-cell function, while 89% of the patients who had no partial remission developed beta-cell function failure. In patients whose partial remission ended, the average C-peptide was still higher than duration-matched patients without partial remission. CONCLUSIONS Patients with partial remission of T1D have a distinct three-phasic pattern of C-peptide decline, other than the widely recognized biphasic pattern. The effect of partial remission still exists after remission ends.
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Affiliation(s)
- Mei Shi
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yuting Xie
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Rong Tang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ting Zhong
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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31
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Bolla AM, Usuelli V, Ben Nasr M, Frigerio S, Loretelli C, D'Addio F, Fiorina P. Next-gen therapeutics to spare and expand beta-cell mass. Curr Opin Pharmacol 2021; 61:77-82. [PMID: 34649215 DOI: 10.1016/j.coph.2021.09.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/02/2021] [Accepted: 09/07/2021] [Indexed: 12/16/2022]
Abstract
The most effective and physiological way to treat hyperglycemia is to restore beta-cell function and to rescue production of endogenous insulin. Increasing evidence suggests that both type 1 and type 2 diabetes are characterized by a significant defect in beta-cell mass, leading to the manifestation of the disease. Novel alternative approaches are needed to spare and expand beta-cell mass in patients with diabetes. This review sets out to describe the latest findings on how to restore the beta-cell mass and function in both forms of diabetes to modulate their progression.
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Affiliation(s)
| | - Vera Usuelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sofia Frigerio
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Cristian Loretelli
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Francesca D'Addio
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy; International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
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32
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Erdem N, Montero E, Roep BO. Breaking and restoring immune tolerance to pancreatic beta-cells in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 2021; 28:397-403. [PMID: 34183540 DOI: 10.1097/med.0000000000000646] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Type 1 diabetes (T1D) results from the loss of immune tolerance to pancreatic beta-cells leading to their destruction. Immune intervention therapies tested in T1D so far delayed progression but failed to restore tolerance, which partly explains their lack of durable clinical efficacy. RECENT FINDINGS The role of beta-cells and islets themselves in dialogue with their micro- and macro-environment including the immune system and the intestinal microbiome is increasingly evident. Indeed, islets can both maintain and break immune tolerance. Some recent immune therapies in cancer that block immune regulation also break tolerance. Induction of immune tolerance requires activating immune activation too, whereas immune suppression precludes this process. Immunotherapy alone my not suffice without engaging islets to restore tolerance and preserve beta-cell function. SUMMARY New insight into the role of islet tissue and its interaction with its environment in preserving or breaking tolerance has contributed to understand the development of islet autoimmunity and T1D. Knowing which factors in islets and the immune system contribute to maintaining, breaking, and restoring the balance in the immune system is critical to prevent initiation and reverse disease progression, and guides the design of novel tolerogenic strategies for durable therapeutic intervention and remission that target both the immune system and distressed islets.
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Affiliation(s)
- Neslihan Erdem
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
- Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Enrique Montero
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
| | - Bart O Roep
- The Arthur Riggs Diabetes & Metabolism Research Institute at the Beckman Research Institute
- Department Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
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Jeffery N, Chambers D, Invergo BM, Ames RM, Harries LW. Changes to the identity of EndoC-βH1 beta cells may be mediated by stress-induced depletion of HNRNPD. Cell Biosci 2021; 11:144. [PMID: 34301309 PMCID: PMC8305497 DOI: 10.1186/s13578-021-00658-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 07/14/2021] [Indexed: 12/02/2022] Open
Abstract
Background Beta cell identity changes occur in the islets of donors with diabetes, but the molecular basis of this remains unclear. Protecting residual functional beta cells from cell identity changes may be beneficial for patients with diabetes. Results A somatostatin-positive cell population was induced in stressed clonal human EndoC-βH1 beta cells and was isolated using FACS. A transcriptomic characterisation of somatostatin-positive cells was then carried out. Gain of somatostatin-positivity was associated with marked dysregulation of the non-coding genome. Very few coding genes were differentially expressed. Potential candidate effector genes were assessed by targeted gene knockdown. Targeted knockdown of the HNRNPD gene induced the emergence of a somatostatin-positive cell population in clonal EndoC-βH1 beta cells comparable with that we have previously reported in stressed cells. Conclusions We report here a role for the HNRNPD gene in determination of beta cell identity in response to cellular stress. These findings widen our understanding of the role of RNA binding proteins and RNA biology in determining cell identity and may be important for protecting remaining beta cell reserve in diabetes. Supplementary Information The online version contains supplementary material available at 10.1186/s13578-021-00658-6.
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Affiliation(s)
- Nicola Jeffery
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK
| | | | | | - Ryan M Ames
- University of Exeter, Stocker Road, Exeter, EX4 4QD, UK
| | - Lorna W Harries
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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35
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Januszewski AS, Cho YH, Joglekar MV, Farr RJ, Scott ES, Wong WKM, Carroll LM, Loh YW, Benitez-Aguirre PZ, Keech AC, O'Neal DN, Craig ME, Hardikar AA, Donaghue KC, Jenkins AJ. Insulin micro-secretion in Type 1 diabetes and related microRNA profiles. Sci Rep 2021; 11:11727. [PMID: 34083567 PMCID: PMC8175359 DOI: 10.1038/s41598-021-90856-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 05/13/2021] [Indexed: 12/22/2022] Open
Abstract
The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors. In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels. Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10–20 years and > 20 years. Plasma C-peptide was measured by ultrasensitive ELISA. Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform. C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON). C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)–upper quartile (UQ)] 5.0 (2.6–28.7) versus 650.9 (401.2–732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ–UQ) 4.2 (2.6–12.2) pmol/L vs. 8.0 (2.3–80.5) pmol/L, p = 0.02, respectively]. In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05).
Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON. Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs. Confirmatory clinical studies and related basic science studies are merited.
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Affiliation(s)
- Andrzej S Januszewski
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. .,Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
| | - Yoon Hi Cho
- Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Mugdha V Joglekar
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia
| | - Ryan J Farr
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Emma S Scott
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Wilson K M Wong
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia
| | - Luke M Carroll
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Yik W Loh
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Paul Z Benitez-Aguirre
- Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Anthony C Keech
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - David N O'Neal
- Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
| | - Maria E Craig
- Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Anandwardhan A Hardikar
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia.,Department of Science and Environment, Roskilde University, Copenhagen, Denmark
| | - Kim C Donaghue
- Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.,Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Alicia J Jenkins
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia. .,Department of Medicine, University of Melbourne, Melbourne, VIC, Australia.
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36
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Szlachcic WJ, Ziojla N, Kizewska DK, Kempa M, Borowiak M. Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing. Front Cell Dev Biol 2021; 9:629212. [PMID: 33996792 PMCID: PMC8116659 DOI: 10.3389/fcell.2021.629212] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/06/2021] [Indexed: 12/16/2022] Open
Abstract
A chronic inability to maintain blood glucose homeostasis leads to diabetes, which can damage multiple organs. The pancreatic islets regulate blood glucose levels through the coordinated action of islet cell-secreted hormones, with the insulin released by β-cells playing a crucial role in this process. Diabetes is caused by insufficient insulin secretion due to β-cell loss, or a pancreatic dysfunction. The restoration of a functional β-cell mass might, therefore, offer a cure. To this end, major efforts are underway to generate human β-cells de novo, in vitro, or in vivo. The efficient generation of functional β-cells requires a comprehensive knowledge of pancreas development, including the mechanisms driving cell fate decisions or endocrine cell maturation. Rapid progress in single-cell RNA sequencing (scRNA-Seq) technologies has brought a new dimension to pancreas development research. These methods can capture the transcriptomes of thousands of individual cells, including rare cell types, subtypes, and transient states. With such massive datasets, it is possible to infer the developmental trajectories of cell transitions and gene regulatory pathways. Here, we summarize recent advances in our understanding of endocrine pancreas development and function from scRNA-Seq studies on developing and adult pancreas and human endocrine differentiation models. We also discuss recent scRNA-Seq findings for the pathological pancreas in diabetes, and their implications for better treatment.
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Affiliation(s)
- Wojciech J. Szlachcic
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Natalia Ziojla
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Dorota K. Kizewska
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Marcelina Kempa
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
| | - Malgorzata Borowiak
- Department of Gene Expression, Institute of Molecular Biology and Biotechnology, Faculty of Biology, Adam Mickiewicz University, Poznań, Poland
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States
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Cheng J, Yin M, Tang X, Yan X, Xie Y, He B, Li X, Zhou Z. Residual β-cell function after 10 years of autoimmune type 1 diabetes: prevalence, possible determinants, and implications for metabolism. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:650. [PMID: 33987348 PMCID: PMC8106063 DOI: 10.21037/atm-20-7471] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Background Type 1 diabetes (T1D) has long been considered a progressive autoimmune disease resulting in the failure of pancreatic β-cell function and absolute endogenous insulin deficiency. However, several studies have demonstrated patients with T1D have detectable C-peptide levels long after diagnosis, which has remarkable clinical significance. Since this issue has not been systematically explored in non-Caucasian populations, we aimed to identify the prevalence of residual β-cell function and its related clinical features in Chinese long-term T1D patients. Methods We enrolled 109 patients with T1D for ≥10 years and administered a mixed-meal tolerance test (MMTT). Fasting and postprandial C-peptide (FCP/PCP) levels were measured to evaluate the insulin secretion function of β-cells. Patients whose FCP and PCP levels were both below the lower detection limit (16.7 pmol/L) were grouped as ‘β-cell function depleted’, while others were thought to have ‘residual β-cell function’. Demographic data, metabolic status, and diabetic complications were compared between patients with or without residual β-cell function. Results 38.5% of subjects retained residual β-cell function, and among those, 33.3% responded to MMTT by a two-fold or greater rise of their FCP levels. Clinical features associated with residual β-cell function were older age of diagnosis [27.5 (interquartile range:11.5–37.0) vs. 17.0 (interquartile range: 8.0–30.0) years, P=0.037], lower HbA1c (64.6±20.3 vs. 72.4±18.5 mmol/mol, P=0.026), and reduced rate of hypoglycemia (23.8% vs. 52.2%, P=0.003). Age of diagnosis was positively correlated with detectable FCP level (r=0.393, P=0.020). Individuals diagnosed after 30 years of age tended to retain residual β-cell function (OR =3.016, P=0.044). We found no association between residual β-cell function and chronic diabetic complications. Conclusions Residual β-cell function can be found in nearly 40% of long-term patients with T1D in China and is associated with older age at diagnosis and better glucose control. The relationship between residual β-cell function and chronic diabetic complications remains to be explored.
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Affiliation(s)
- Jin Cheng
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Min Yin
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiaohan Tang
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xiang Yan
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yuting Xie
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Binbin He
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Disease, Key Laboratory of Diabetes Immunology, Ministry of Education, Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Pinheiro MM, Pinheiro FMM, Diniz SN, Fabbri A, Infante M. Combination of vitamin D and dipeptidyl peptidase-4 inhibitors (VIDPP-4i) as an immunomodulation therapy for autoimmune diabetes. Int Immunopharmacol 2021; 95:107518. [PMID: 33756226 DOI: 10.1016/j.intimp.2021.107518] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/15/2021] [Accepted: 02/16/2021] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) and latent autoimmune diabetes in adults (LADA) represent the most common types of autoimmune diabetes and are characterized by different age of onset, degrees of immune-mediated destruction of pancreatic beta cells and rates of disease progression towards insulin dependence. Several immunotherapies aimed to counteract autoimmune responses against beta cells and preserve beta-cell function are currently being investigated, particularly in T1D. Preliminary findings suggest a potential role of combination therapy with vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors (VIDPP-4i) in preserving beta-cell function in autoimmune diabetes. This manuscript aims to provide a comprehensive overview of the immunomodulatory properties of vitamin D and DPP-4 inhibitors, as well as the rationale for investigation of their combined use as an immunomodulation therapy for autoimmune diabetes.
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Affiliation(s)
- Marcelo Maia Pinheiro
- UNIVAG, University Center, Dom Orlando Chaves Ave, 2655 - Cristo Rei, Várzea Grande, 78118-000 Mato Grosso, Brazil; Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil.
| | - Felipe Moura Maia Pinheiro
- Hospital de Base, Faculdade de Medicina de São José do Rio Preto FAMERP - SP, 5546, Brigadeiro Faria Lima Ave, Vila São Pedro, São José do Rio Preto, 15015-500 São Paulo, Brazil
| | - Susana Nogueira Diniz
- Universidade Anhanguera de São Paulo - SP, 3305, Raimundo Pereira de Magalhães Ave., Pirituba, São Paulo, 05145-200 São Paulo, Brazil
| | - Andrea Fabbri
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy
| | - Marco Infante
- Diabetes Research Institute Federation (DRIF), Division of Endocrinology and Diabetes, CTO Andrea Alesini Hospital, ASL Roma 2, Department of Systems Medicine, University of Rome Tor Vergata, Via San Nemesio 21, 00145 Rome, Italy; UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant'Alessandro, 8, 00131 Rome, Italy; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via San Nemesio 21, 00145 Rome, Italy.
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39
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Wiedeman AE, Speake C, Long SA. The many faces of islet antigen-specific CD8 T cells: clues to clinical outcome in type 1 diabetes. Immunol Cell Biol 2021; 99:475-485. [PMID: 33483981 PMCID: PMC8248166 DOI: 10.1111/imcb.12437] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 01/07/2021] [Accepted: 01/20/2021] [Indexed: 11/26/2022]
Abstract
Immune monitoring enables a better understanding of disease processes and response to therapy, but has been challenging in the setting of chronic autoimmunity because of unknown etiology, variable and protracted kinetics of the disease process, heterogeneity across patients and the complexity of immune interactions. To begin to parse this complexity, we focus here on type 1 diabetes (T1D) and CD8 T cells as a cell type that has features that are associated with different stages of disease, rates of progression and response to therapy. Specifically, we discuss the current understanding of the role of autoreactive CD8 T cells in disease outcome, which implicates particular CD8 functional subsets, rather than unique antigens or total number of autoreactive T cells. Next, we discuss how autoreactive CD8 T‐cell features can be reflected in measures of global CD8 T cells, and then pull these concepts together by highlighting immune therapies recently shown to modulate both CD8 T cells and disease progression. We end by discussing outstanding questions about the role of specific subsets of autoreactive CD8 T cells in disease progression and how they may be optimally modulated to treat and prevent T1D.
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Affiliation(s)
- Alice E Wiedeman
- Translational Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA
| | - Cate Speake
- Interventional Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA
| | - Sarah Alice Long
- Translational Immunology, Benaroya Research Institute, 1201 9th Ave, Seattle, WA, 98101, USA
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40
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López–Noriega L, Rutter GA. Long Non-Coding RNAs as Key Modulators of Pancreatic β-Cell Mass and Function. Front Endocrinol (Lausanne) 2021; 11:610213. [PMID: 33628198 PMCID: PMC7897662 DOI: 10.3389/fendo.2020.610213] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 12/21/2020] [Indexed: 12/16/2022] Open
Abstract
Numerous studies have sought to decipher the genetic and other mechanisms contributing to β-cell loss and dysfunction in diabetes mellitus. However, we have yet to fully understand the etiology of the disease or to develop satisfactory treatments. Since the majority of diabetes susceptibility loci are mapped to non-coding regions within the genome, understanding the functions of non-coding RNAs in β-cell biology might provide crucial insights into the pathogenesis of type 1 (T1D) and type 2 (T2D) diabetes. During the past decade, numerous studies have indicated that long non-coding RNAs play important roles in the maintenance of β-cell mass and function. Indeed, lncRNAs have been shown to be involved in controlling β-cell proliferation during development and/or β-cell compensation in response to hyperglycaemia. LncRNAs such as TUG-1 and MEG3 play a role in both β-cell apoptosis and function, while others sensitize β-cells to apoptosis in response to stress signals. In addition, several long non-coding RNAs have been shown to regulate the expression of β-cell-enriched transcription factors in cis or in trans. In this review, we provide an overview of the roles of lncRNAs in maintaining β-function and mass, and discuss their relevance in the development of diabetes.
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Affiliation(s)
- Livia López–Noriega
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Diabetes, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Diabetes, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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41
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Pearce SHS, Gan EH, Napier C. MANAGEMENT OF ENDOCRINE DISEASE: Residual adrenal function in Addison's disease. Eur J Endocrinol 2021; 184:R61-R67. [PMID: 33306039 PMCID: PMC7849375 DOI: 10.1530/eje-20-0894] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Accepted: 12/08/2020] [Indexed: 11/08/2022]
Abstract
Over the last 10 years, evidence has accumulated that autoimmune Addison's disease (AAD) is a heterogeneous disease. Residual adrenal function, characterised by persistent secretion of cortisol, other glucocorticoids and mineralocorticoids is present in around 30% of patients with established AAD, and appears commoner in men. This persistent steroidogenesis is present in some patients with AAD for more than 20 years, but it is commoner in people with shorter disease duration. The clinical significance of residual adrenal function is not fully clear at the moment, but as it signifies an intact adrenocortical stem cell population, it opens up the possibility of regeneration of adrenal steroidogenesis and improvement in adrenal failure for some patients.
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Affiliation(s)
- Simon H S Pearce
- Translational and Clinical Research Institute, Newcastle University, Newcastle, UK
- Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Correspondence should be addressed to S H S Pearce;
| | - Earn H Gan
- Translational and Clinical Research Institute, Newcastle University, Newcastle, UK
- Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Catherine Napier
- Endocrine Unit, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
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Jeyam A, Colhoun H, McGurnaghan S, Blackbourn L, McDonald TJ, Palmer CNA, McKnight JA, Strachan MWJ, Patrick AW, Chalmers J, Lindsay RS, Petrie JR, Thekkepat S, Collier A, MacRury S, McKeigue PM. Clinical Impact of Residual C-Peptide Secretion in Type 1 Diabetes on Glycemia and Microvascular Complications. Diabetes Care 2021; 44:390-398. [PMID: 33303639 DOI: 10.2337/dc20-0567] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 11/03/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To quantify the relationship of residual C-peptide secretion to glycemic outcomes and microvascular complications in type 1 diabetes. RESEARCH DESIGN AND METHODS C-peptide was measured in an untimed blood sample in the Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) cohort of 6,076 people with type 1 diabetes monitored for an average of 5.2 years. RESULTS In regression models adjusted for age at onset and duration, effect sizes for C-peptide ≥200 vs. <5 pmol/L were as follows: insulin dose at baseline, 27% lower (P = 2 × 10-39); HbA1c during follow-up, 4.9 mmol/mol lower (P = 3 × 10-13); hazard ratio for hospital admission for diabetic ketoacidosis during follow-up, 0.44 (P = 0.0001); odds ratio for incident retinopathy, 0.51 (P = 0.0003). Effects on the risk of serious hypoglycemic episodes were detectable at lower levels of C-peptide, and the form of the relationship was continuous down to the limit of detection (3 pmol/L). In regression models contrasting C-peptide 30 to <200 pmol/L with <5 pmol/L, the odds ratio for self-report of at least one serious hypoglycemic episode in the last year was 0.56 (P = 6 × 10-8), and the hazard ratio for hospital admission for hypoglycemia during follow-up was 0.52 (P = 0.03). CONCLUSIONS These results in a large representative cohort suggest that even minimal residual C-peptide secretion could have clinical benefit in type 1 diabetes, in contrast to a follow-up study of the Diabetes Control and Complications Trial (DCCT) intensively treated cohort where an effect on hypoglycemia was seen only at C-peptide levels ≥130 pmol/L. This has obvious implications for the design and evaluation of trials of interventions to preserve or restore pancreatic islet function in type 1 diabetes.
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Affiliation(s)
- Anita Jeyam
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, U.K
| | - Helen Colhoun
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, U.K
| | - Stuart McGurnaghan
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, U.K
| | - Luke Blackbourn
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, U.K
| | | | | | | | | | | | | | - Robert S Lindsay
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | - John R Petrie
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, U.K
| | | | | | - Sandra MacRury
- National Health Service Highland Diabetes Centre, Inverness, U.K
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Bolla AM, Gandolfi A, Borgonovo E, Laurenzi A, Caretto A, Molinari C, Catalano RS, Bianconi E, Monti P, Sordi V, Pellegrini S, Lampasona V, Costa S, Scavini M, Bosi E, Piemonti L. Rapamycin Plus Vildagliptin to Recover β-Cell Function in Long-Standing Type 1 Diabetes: A Double-Blind, Randomized Trial. J Clin Endocrinol Metab 2021; 106:e507-e519. [PMID: 33124663 DOI: 10.1210/clinem/dgaa791] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Indexed: 02/13/2023]
Abstract
AIM The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores β-cell function in patients with long-standing type 1 diabetes. METHODS A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutes > 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile. RESULTS Fifty-five patients were randomly assigned to group 1 (n = 18), group 2 (n = 19), or group 3 (n = 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (P = .013), from 0.59 to 0.51 U/kg/day in group 3 (P < .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; P = .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; P = .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. CONCLUSIONS Rapamycin reduced insulin requirement, but did not restore β-cell function in patients with long-standing type 1 diabetes.
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Affiliation(s)
- Andrea Mario Bolla
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Alessandra Gandolfi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Andrea Laurenzi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Amelia Caretto
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Chiara Molinari
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Eleonora Bianconi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Paolo Monti
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Valeria Sordi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Silvia Pellegrini
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Vito Lampasona
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Sabrina Costa
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Marina Scavini
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Emanuele Bosi
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
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44
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Brawerman G, Thompson PJ. Beta Cell Therapies for Preventing Type 1 Diabetes: From Bench to Bedside. Biomolecules 2020; 10:E1681. [PMID: 33339173 PMCID: PMC7765619 DOI: 10.3390/biom10121681] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/09/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
Type 1 diabetes (T1D) is a chronic metabolic disease characterized by insulin deficiency, generally resulting from progressive autoimmune-mediated destruction of pancreatic beta cells. While the phenomenon of beta cell autoimmunity continues to be an active area of investigation, recent evidence suggests that beta cell stress responses are also important contributors to disease onset. Here we review the pathways driving different kinds of beta cell dysfunction and their respective therapeutic targets in the prevention of T1D. We discuss opportunities and important open questions around the effectiveness of beta cell therapies and challenges for clinical utility. We further evaluate ways in which beta cell drug therapy could be combined with immunotherapy for preventing T1D in light of our growing appreciation of disease heterogeneity and patient endotypes. Ultimately, the emergence of pharmacologic beta cell therapies for T1D have armed us with new tools and closing the knowledge gaps in T1D etiology will be essential for maximizing the potential of these approaches.
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Affiliation(s)
- Gabriel Brawerman
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada;
- Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
| | - Peter J. Thompson
- Department of Physiology and Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 3P4, Canada;
- Children’s Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada
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Pöllänen PM, Ryhänen SJ, Toppari J, Ilonen J, Vähäsalo P, Veijola R, Siljander H, Knip M. Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years. J Clin Endocrinol Metab 2020; 105:5901133. [PMID: 32882033 PMCID: PMC7686032 DOI: 10.1210/clinem/dgaa624] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/31/2020] [Indexed: 01/23/2023]
Abstract
CONTEXT We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context. DESIGN HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. RESULTS By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01). CONCLUSIONS In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.
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Affiliation(s)
- Petra M Pöllänen
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Samppa J Ryhänen
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, and Institute of Biomedicine and Centre for Population Health Research, University of Turku, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland
| | - Paula Vähäsalo
- Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Heli Siljander
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Correspondence and Reprint Requests: Mikael Knip, MD, PhD, Children’s Hospital, University of Helsinki, P.O. Box 22 (Stenbäckinkatu 11), FI-00014 Helsinki, Finland. E-mail:
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Munshi MN, Meneilly GS, Rodríguez-Mañas L, Close KL, Conlin PR, Cukierman-Yaffe T, Forbes A, Ganda OP, Kahn CR, Huang E, Laffel LM, Lee CG, Lee S, Nathan DM, Pandya N, Pratley R, Gabbay R, Sinclair AJ. Diabetes in ageing: pathways for developing the evidence base for clinical guidance. Lancet Diabetes Endocrinol 2020; 8:855-867. [PMID: 32946822 PMCID: PMC8223534 DOI: 10.1016/s2213-8587(20)30230-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/12/2020] [Accepted: 06/19/2020] [Indexed: 02/07/2023]
Abstract
Older adults with diabetes are heterogeneous in their medical, functional, and cognitive status, and require careful individualisation of their treatment regimens. However, in the absence of detailed information from clinical trials involving older people with varying characteristics, there is little evidence-based guidance, which is a notable limitation of current approaches to care. It is important to recognise that older people with diabetes might vary in their profiles according to age category, functional health, presence of frailty, and comorbidity profiles. In addition, all older adults with diabetes require an individualised approach to care, ranging from robust individuals to those residing in care homes with a short life expectancy, those requiring palliative care, or those requiring end-of-life management. In this Review, our multidisciplinary team of experts describes the current evidence in several important areas in geriatric diabetes, and outlines key research gaps and research questions in each of these areas with the aim to develop evidence-based recommendations to improve the outcomes of interest in older adults.
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Affiliation(s)
- Medha N Munshi
- Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA.
| | | | | | - Kelly L Close
- The diaTribe Foundation San Francisco, CA, USA; Close Concerns, San Francisco, CA, USA
| | - Paul R Conlin
- Harvard Medical School, Boston, MA, USA; Veteran Affairs Boston Healthcare System, Boston, MA, USA
| | - Tali Cukierman-Yaffe
- Division of Endocrinology, Diabetes and Metabolism, Gertner Institute, Ramat Gan, Israel; Sheba Medical Centre, Ramat Gan, Israel; Epidemiology Department, Sackler School of Medicine, Herczeg Institute on Aging, Tel Aviv University, Tel Aviv, Israel
| | | | - Om P Ganda
- Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA
| | - C Ronald Kahn
- Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA
| | - Elbert Huang
- Center for Chronic Disease Research and Policy, Section of General Internal Medicine, University of Chicago, Chicago, IL, USA
| | - Lori M Laffel
- Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA
| | - Christine G Lee
- Division of Diabetes, Endocrinology and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Sei Lee
- University of California San Francisco, San Francisco, CA, USA; Geriatrics and Extended Care, San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA
| | - David M Nathan
- Harvard Medical School, Boston, MA, USA; Diabetes Research Center and Clinical Research Center, Massachusetts General Hospital, Boston, MA, USA
| | - Naushira Pandya
- Department of Geriatrics, Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Aventura Hospital, Aventura, FL, USA
| | - Richard Pratley
- AdventHealth, AdventHealth Diabetes Institute, AdventHealth Translational Research Institute, Orlando, FL, USA
| | - Robert Gabbay
- Harvard Medical School, Boston, MA, USA; Joslin Diabetes Center, Boston, MA, USA
| | - Alan J Sinclair
- King's College London, London, UK; Diabetes Frail, London, UK
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Taylor GS, Smith K, Capper TE, Scragg JH, Bashir A, Flatt A, Stevenson EJ, McDonald TJ, Oram RA, Shaw JA, West DJ. Postexercise Glycemic Control in Type 1 Diabetes Is Associated With Residual β-Cell Function. Diabetes Care 2020; 43:2362-2370. [PMID: 32747405 PMCID: PMC7510016 DOI: 10.2337/dc20-0300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 06/28/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate the impact of residual β-cell function on continuous glucose monitoring (CGM) outcomes following acute exercise in people with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Thirty participants with T1D for ≥3 years were recruited. First, participants wore a blinded CGM unit for 7 days of free-living data capture. Second, a 3-h mixed-meal test assessed stimulated C-peptide and glucagon. Peak C-peptide was used to allocate participants into undetectable (Cpepund <3 pmol/L), low (Cpeplow 3-200 pmol/L), or high (Cpephigh >200 pmol/L) C-peptide groups. Finally, participants completed 45 min of incline treadmill walking at 60% VO2peak followed by a further 48-h CGM capture. RESULTS CGM parameters were comparable across groups during the free-living observation week. In the 12- and 24-h postexercise periods (12 h and 24 h), the Cpephigh group had a significantly greater amount of time spent with glucose 3.9-10 mmol/L (12 h, 73.5 ± 27.6%; 24 h, 76.3 ± 19.2%) compared with Cpeplow (12 h, 43.6 ± 26.1%, P = 0.027; 24 h, 52.3 ± 25.0%, P = 0.067) or Cpepund (12 h, 40.6 ± 17.0%, P = 0.010; 24 h, 51.3 ± 22.3%, P = 0.041). Time spent in hyperglycemia (12 h and 24 h glucose >10 and >13.9 mmol/L, P < 0.05) and glycemic variability (12 h and 24 h SD, P < 0.01) were significantly lower in the Cpephigh group compared with Cpepund and Cpeplow. Change in CGM outcomes from pre-exercise to 24-h postexercise was divergent: Cpepund and Cpeplow experienced worsening (glucose 3.9-10 mmol/L: -9.1% and -16.2%, respectively), with Cpephigh experiencing improvement (+12.1%) (P = 0.017). CONCLUSIONS Residual β-cell function may partially explain the interindividual variation in the acute glycemic benefits of exercise in individuals with T1D. Quantifying C-peptide could aid in providing personalized and targeted support for exercising patients.
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Affiliation(s)
- Guy S Taylor
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Kieran Smith
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Tess E Capper
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K.,Centre for Public Health, Queen's University Belfast, Belfast, U.K
| | - Jadine H Scragg
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Ayat Bashir
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Anneliese Flatt
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Emma J Stevenson
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K
| | - Timothy J McDonald
- National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, U.K.,Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K
| | - Richard A Oram
- National Institute for Health Research Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, U.K.,Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K
| | - James A Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, U.K.
| | - Daniel J West
- Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, U.K.
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Demine S, Schulte ML, Territo PR, Eizirik DL. Beta Cell Imaging-From Pre-Clinical Validation to First in Man Testing. Int J Mol Sci 2020; 21:E7274. [PMID: 33019671 PMCID: PMC7582644 DOI: 10.3390/ijms21197274] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/21/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
There are presently no reliable ways to quantify human pancreatic beta cell mass (BCM) in vivo, which prevents an accurate understanding of the progressive beta cell loss in diabetes or following islet transplantation. Furthermore, the lack of beta cell imaging hampers the evaluation of the impact of new drugs aiming to prevent beta cell loss or to restore BCM in diabetes. We presently discuss the potential value of BCM determination as a cornerstone for individualized therapies in diabetes, describe the presently available probes for human BCM evaluation, and discuss our approach for the discovery of novel beta cell biomarkers, based on the determination of specific splice variants present in human beta cells. This has already led to the identification of DPP6 and FXYD2ga as two promising targets for human BCM imaging, and is followed by a discussion of potential safety issues, the role for radiochemistry in the improvement of BCM imaging, and concludes with an overview of the different steps from pre-clinical validation to a first-in-man trial for novel tracers.
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Affiliation(s)
- Stephane Demine
- Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA;
| | - Michael L. Schulte
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (M.L.S.); (P.R.T.)
| | - Paul R. Territo
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (M.L.S.); (P.R.T.)
- Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Decio L. Eizirik
- Indiana Biosciences Research Institute, Indianapolis, IN 46202, USA;
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 1070 Brussels, Belgium
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Translation of curative therapy concepts with T cell and cytokine antibody combinations for type 1 diabetes reversal in the IDDM rat. J Mol Med (Berl) 2020; 98:1125-1137. [PMID: 32607871 PMCID: PMC8550584 DOI: 10.1007/s00109-020-01941-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/09/2020] [Accepted: 06/17/2020] [Indexed: 11/21/2022]
Abstract
Abstract Proinflammatory cytokines released from the pancreatic islet immune cell infiltrate in type 1 diabetes (T1D) cause insulinopenia as a result of severe beta cell loss due to apoptosis. Diabetes prevention strategies targeting different cytokines with antibodies in combination with a T cell antibody, anti-TCR, have been assessed for therapy success in the LEW.1AR1-iddm (IDDM) rat, an animal model of human T1D. Immediately after diabetes manifestation, antibody combination therapies were initiated over 5 days with anti-TNF-α (tumour necrosis factor), anti-IL-1β (interleukin), or anti-IFN-γ (interferon) together with anti-TCR for the reversal of the diabetic metabolic state in the IDDM rat. Anti-TCR alone showed only a very limited therapy success with respect to a reduction of immune cell infiltration and beta cell mass regeneration. Anti-TCR combinations with anti-IL-1β or anti-IFN-γ were also not able to abolish the increased beta cell apoptosis rate and the activated immune cell infiltrate leading to a permanent beta cell loss. In contrast, all anti-TCR combinations with anti-TNF-α provided sustained therapy success over 60 to 360 days. The triple combination of anti-TCR with anti-TNF-α plus anti-IL-1β was most effective in regaining sustained normoglycaemia with an intact islet structure in a completely infiltration-free pancreas and with a normal beta cell mass. Besides the triple combination, the double antibody combination of anti-TCR with anti-TNF-α proved to be the most suited therapy for reversal of the T1D metabolic state due to effective beta cell regeneration in an infiltration free pancreas. Key messages
Anti-TCR is a cornerstone in combination therapy for autoimmune diabetes reversal. The combination of anti-TCR with anti-TNF-α was most effective in reversing islet immune cell infiltration. Anti-TCR combined with anti-IL-1β was not effective in this respect. The combination of anti-TCR with anti-TNF-α showed a sustained effect over 1 year. Electronic supplementary material The online version of this article (10.1007/s00109-020-01941-8) contains supplementary material, which is available to authorized users.
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50
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Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol 2020; 16:349-362. [PMID: 32398822 DOI: 10.1038/s41574-020-0355-7] [Citation(s) in RCA: 470] [Impact Index Per Article: 94.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/24/2020] [Indexed: 12/12/2022]
Abstract
Loss of functional β-cell mass is the key mechanism leading to the two main forms of diabetes mellitus - type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Understanding the mechanisms behind β-cell failure is critical to prevent or revert disease. Basic pathogenic differences exist in the two forms of diabetes mellitus; T1DM is immune mediated and T2DM is mediated by metabolic mechanisms. These mechanisms differentially affect early β-cell dysfunction and eventual fate. Over the past decade, major advances have been made in the field, mostly delivered by studies on β-cells in human disease. These advances include studies of islet morphology and human β-cell gene expression in T1DM and T2DM, the identification and characterization of the role of T1DM and T2DM candidate genes at the β-cell level and the endoplasmic reticulum stress signalling that contributes to β-cell failure in T1DM (mostly IRE1 driven) and T2DM (mostly PERK-eIF2α dependent). Here, we review these new findings, focusing on studies performed on human β-cells or on samples obtained from patients with diabetes mellitus.
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Affiliation(s)
- Décio L Eizirik
- ULB Center for Diabetes Research, Welbio Investigator, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium.
- Indiana Biosciences Research Institute (IBRI), Indianapolis, IN, USA.
| | - Lorenzo Pasquali
- Endocrine Regulatory Genomics, Department of Experimental & Health Sciences, University Pompeu Fabra, Barcelona, Spain.
- Germans Trias i Pujol University Hospital and Research Institute, Badalona, Spain.
- Josep Carreras Leukaemia Research Institute, Barcelona, Spain.
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium.
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