|
1
|
Camenzuli JA, Sammut MJ, Tijo T, Melling CWJ. Effects of acute aerobic exercise on skeletal muscle and liver glucose metabolism in male rodents with type 1 diabetes. Can J Physiol Pharmacol 2025; 103:123-133. [PMID: 39813664 DOI: 10.1139/cjpp-2024-0226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2025]
Abstract
Aerobic exercise (AE) is associated with a significant hypoglycemia risk in individuals with type 1 diabetes mellitus (T1DM). However, the mechanisms in the liver and skeletal muscle governing exercise-induced hypoglycemia in T1DM are poorly understood. This study examined the effects of a 60-min bout of AE on hepatic and muscle glucose metabolism in T1DM rats. Nineteen male Sprague-Dawley rats were divided into sedentary (SC; n = 5) and T1DM (DSC; n = 14) groups. T1DM rats were subcategorized into pre-exercise (DPRE; n = 6) and post-exercise (DPOST; n = 8). DPOST were sacrificed immediately after 60 min of AE. Results demonstrate that DPOST animals experienced reductions in BG following 30 and 60 min of AE compared to pre-exercise. Both DPRE and DPOST animals exhibited lower hepatic glycogen content, while muscle glycogen did not differ, suggesting impaired glycogenolysis in T1DM. Hepatic glucose-6-phosphatase content, and muscle and hepatic protein kinase B phosphorylation were significantly greater in DPOST animals, suggesting elevated gluconeogenesis and insulin stimulation during exercise. Glycogen phosphorylase activity did not differ between groups. These data suggest that drops in BG during AE in T1DM were due to lower glycogen levels in the liver and muscle and a lack of muscle glycogen utilization; leading to a reliance on gluconeogenesis and BG.
Collapse
Affiliation(s)
- Justin A Camenzuli
- School of Kinesiology, Faculty of Health Sciences, Western University, ON N6A 3K7, Canada
| | - Mitchell J Sammut
- School of Kinesiology, Faculty of Health Sciences, Western University, ON N6A 3K7, Canada
| | - Theres Tijo
- School of Kinesiology, Faculty of Health Sciences, Western University, ON N6A 3K7, Canada
| | - C W James Melling
- School of Kinesiology, Faculty of Health Sciences, Western University, ON N6A 3K7, Canada
- Department of Physiology & Pharmacology, Schulich School of Medicine & Dentistry, Western University, ON N6A 3K7, Canada
| |
Collapse
|
|
2
|
Dao GM, Kowalski GM, Bruce CR, O'Neal DN, Smart CE, Zaharieva DP, Hennessy DT, Zhao S, Morrison DJ. The Glycemic Impact of Protein Ingestion in People With Type 1 Diabetes. Diabetes Care 2025; 48:509-518. [PMID: 39951019 DOI: 10.2337/dci24-0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/07/2025] [Indexed: 03/23/2025]
Abstract
In individuals with type 1 diabetes, carbohydrate is commonly recognized as the primary macronutrient influencing postprandial glucose levels. Accumulating evidence indicates that protein ingestion also contributes to the increment in postprandial glucose levels, despite endocrine and metabolic responses different from those with carbohydrate ingestion. However, findings regarding protein ingestion's glycemic effect in people with type 1 diabetes are equivocal, with the magnitude of glycemic response seemingly dependent on the rate of absorption and composition of protein ingested. Therefore, the aim of this article is to outline the physiological mechanisms by which ingested protein influences blood glucose regulation in individuals with type 1 diabetes and provide clinical implications on use of dietary protein in the context of glycemic management. Specifically, protein ingestion raises plasma amino acid levels, which directly or indirectly (via gut hormones) stimulates glucagon secretion. Together with the increase in gluconeogenic precursors and an absent endogenous insulin response in individuals with type 1 diabetes, this provides a synergistic physiological environment for increased endogenous glucose production and subsequently increasing circulating glucose levels for several hours. While there is a dearth of well-controlled studies in this area, we provide clinical implications and directions for future research regarding the potential for using ingestion of fast-absorbing protein (such as whey protein) as a tool to prevent and mitigate overnight- and exercise-induced hypoglycemia in people with type 1 diabetes.
Collapse
Affiliation(s)
- Giang M Dao
- Institute for Physical Activity and Nutrition, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Greg M Kowalski
- Institute for Physical Activity and Nutrition, School of Medicine, Deakin University, Geelong, Victoria, Australia
| | - Clinton R Bruce
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
| | - David N O'Neal
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Carmel E Smart
- Department of Pediatrics Diabetes and Endocrinology, John Hunter Children's Hospital, Newcastle, New South Wales, Australia
| | - Dessi P Zaharieva
- Division of Pediatric Endocrinology, Department of Pediatrics, Stanford University, Stanford, CA
| | - Declan T Hennessy
- Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Victoria, Australia
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Sam Zhao
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dale J Morrison
- Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
| |
Collapse
|
|
3
|
Henriksen K, Jørgensen A, Kaur S, Gerwig R, Brøgger Svane CA, Knop FK, Størling J. Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells. Mol Cell Endocrinol 2025; 602:112522. [PMID: 40122442 DOI: 10.1016/j.mce.2025.112522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 02/03/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its cytoprotective effects shown in rodent beta cells. To further increase our understanding of GIP's effects on human beta cells, we here examined the functional, protective, and transcriptomic effects of GIP in human EndoC-βH5 beta cells and isolated human islets in the presence or absence of proinflammatory cytokines (interferon (IFN)-γ ± interleukin (IL)-1β) as a mimic of type 1 diabetes. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets at high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis in EndoC-βH5 cells or human islets, and GIP did not protect against cytokine-induced functional impairment in EndoC-βH5 cells. GIP treatment of human islets for 24 h had no effects on the transcriptome and did not modulate cytokine-induced transcriptional changes. However, GIP augmented IL-1β + IFNγ-induced secretion of interleukin (IL)-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our findings indicate that GIP neither exerts cytoprotective effects against cytokines nor modulate the transcriptome of human islets. GIP may, however, exert selective modulatory effects on secreted inflammatory factors from cytokine-exposed beta cells and islets.
Collapse
Affiliation(s)
- Kristine Henriksen
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Anne Jørgensen
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simranjeet Kaur
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Rebekka Gerwig
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Cecilie Amalie Brøgger Svane
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - 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
| | - Joachim Størling
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
4
|
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.
Collapse
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.)
| | | | | | | | | |
Collapse
|
|
5
|
Ambalavanan J, Rusticelli J, Isaacs D, Xiao H, Bena J, Babiuch C, Lansang MC. Leveraging Continuous Glucose Monitoring Data as an Additional Source for Glucagon Prescription Behavior. Endocr Pract 2025; 31:65-71. [PMID: 39490582 DOI: 10.1016/j.eprac.2024.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/11/2024] [Accepted: 10/21/2024] [Indexed: 11/05/2024]
Abstract
OBJECTIVE Hypoglycemia can be life-threatening for patients with diabetes. We aimed to 1) evaluate percentage of glucagon prescription in patients with hypoglycemia on continuous glucose monitoring (CGM) reports, and 2) determine incident glucagon prescription after an educational letter delivered to the providers. RESEARCH DESIGN AND METHODS The study had 2 components - retrospective chart review and a quality improvement (QI) component. Chart review was conducted from March to October 2023 on adult patients in a tertiary care health system with type 1 diabetes or type 2 diabetes on insulin, sulfonylurea, or meglitinide. Percentages of pre-existing and incident glucagon prescription were evaluated. For the QI, we contacted providers whose patients had hypoglycemia defined as time below range ≥ 4% on CGM reports without a glucagon prescription and shared the American Diabetes Association Standards of Care on hypoglycemia along with information about various forms of glucagon. Data on glucagon prescription were collected 4 weeks later. RESULTS Of the 1543 patients included, 170 had time below range ≥4%. Among them, 37% had pre-existing prescription and 14% incident glucagon prescription, compared with patients without hypoglycemia (P < .001). Pre-existing or incident glucagon prescription was seen in 28% without hypoglycemia, 38% with mild, 49% with moderate, and 63% with severe hypoglycemia (P < .001 mild vs severe; moderate vs no hypoglycemia; and severe vs no hypoglycemia). Among 70 patients whose providers received education, 27 (39%) prescribed glucagon. Glucagon emergency kit, glucagon autoinjector, and inhaled glucagon were top choices. CONCLUSION Glucagon prescription remains suboptimal among patients with hypoglycemia on CGM reports. Provider engagement via QI can increase glucagon prescription.
Collapse
Affiliation(s)
| | - Jill Rusticelli
- Endocrinology, Diabetes & Metabolism, Medical Sub-specialty Institute, Cleveland Clinic, Cleveland, Ohio
| | - Diana Isaacs
- Endocrinology, Diabetes & Metabolism, Medical Sub-specialty Institute, Cleveland Clinic, Cleveland, Ohio
| | - Huijun Xiao
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - James Bena
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | | | - M Cecilia Lansang
- Endocrinology, Diabetes & Metabolism, Medical Sub-specialty Institute, Cleveland Clinic, Cleveland, Ohio.
| |
Collapse
|
|
6
|
Mirghani HO. Glucagon-like peptide-1 agonists: Role of the gut in hypoglycemia unawareness, and the rationale in type 1 diabetes. World J Diabetes 2024; 15:2167-2172. [PMID: 39582561 PMCID: PMC11580574 DOI: 10.4239/wjd.v15.i11.2167] [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: 07/12/2024] [Revised: 08/30/2024] [Accepted: 09/05/2024] [Indexed: 10/16/2024] Open
Abstract
Type 1 diabetes is increasing and the majority of patients have poor glycemic control. Although advanced technology and nanoparticle use have greatly enhanced insulin delivery and glucose monitoring, weight gain and hypoglycemia remain major challenges and a constant source of concern for patients with type 1 diabetes. Type 1 diabetes shares some pathophysiology with type 2 diabetes, and an overlap has been reported. The above observation created great interest in glucagon-like peptide-1 receptor agonists (GLP-1) as adjuvants for type 1 diabetes. Previous trials confirmed the positive influence of GLP-1 agonists on β cell function. However, hypoglycemia unawareness and dysregulated glucagon response have been previously reported in patients with recurrent hypoglycemia using GLP-1 agonists. Jin et al found that the source of glucagon dysregulation due to GLP-1 agonists resides in the gut. Plausible explanations could be gut nervous system dysregulation or gut microbiota disruption. This review evaluates the potential of GLP-1 agonists in managing type 1 diabetes, particularly focusing on their impact on glycemic control, weight management, and glucagon dysregulation. We provide a broader insight into the problem of type 1 diabetes mellitus management in the light of recent findings and provide future research directions.
Collapse
Affiliation(s)
- Hyder O Mirghani
- Internal Medicine, University of Tabuk, Tabuk 51941, Tabuk, Saudi Arabia
| |
Collapse
|
|
7
|
Perez-Frances M, Bru-Tari E, Cohrs C, Abate MV, van Gurp L, Furuyama K, Speier S, Thorel F, Herrera PL. Regulated and adaptive in vivo insulin secretion from islets only containing β-cells. Nat Metab 2024; 6:1791-1806. [PMID: 39169271 PMCID: PMC11422169 DOI: 10.1038/s42255-024-01114-8] [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: 04/26/2023] [Accepted: 07/22/2024] [Indexed: 08/23/2024]
Abstract
Insulin-producing β-cells in pancreatic islets are regulated by systemic cues and, locally, by adjacent islet hormone-producing 'non-β-cells' (namely α-cells, δ-cells and γ-cells). Yet whether the non-β-cells are required for accurate insulin secretion is unclear. Here, we studied mice in which adult islets are exclusively composed of β-cells and human pseudoislets containing only primary β-cells. Mice lacking non-β-cells had optimal blood glucose regulation, enhanced glucose tolerance, insulin sensitivity and restricted body weight gain under a high-fat diet. The insulin secretion dynamics in islets composed of only β-cells was comparable to that in intact islets. Similarly, human β-cell pseudoislets retained the glucose-regulated mitochondrial respiration, insulin secretion and exendin-4 responses of entire islets. The findings indicate that non-β-cells are dispensable for blood glucose homeostasis and β-cell function. These results support efforts aimed at developing diabetes treatments by generating β-like clusters devoid of non-β-cells, such as from pluripotent stem cells differentiated in vitro or by reprograming non-β-cells into insulin producers in situ.
Collapse
Affiliation(s)
- Marta Perez-Frances
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Eva Bru-Tari
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Christian Cohrs
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Maria Valentina Abate
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Léon van Gurp
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Kenichiro Furuyama
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Stephan Speier
- Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Clinic Carl Gustav Carus of Technische Universität Dresden, Helmholtz Zentrum München, Neuherberg, Germany
| | - Fabrizio Thorel
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pedro L Herrera
- Department of Genetic Medicine and Development, iGE3 and Centre facultaire du diabète, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
| |
Collapse
|
|
8
|
Zanfrini E, Bandral M, Jarc L, Ramirez-Torres MA, Pezzolla D, Kufrin V, Rodriguez-Aznar E, Avila AKM, Cohrs C, Speier S, Neumann K, Gavalas A. Generation and application of novel hES cell reporter lines for the differentiation and maturation of hPS cell-derived islet-like clusters. Sci Rep 2024; 14:19863. [PMID: 39191834 DOI: 10.1038/s41598-024-69645-4] [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: 10/27/2023] [Accepted: 08/07/2024] [Indexed: 08/29/2024] Open
Abstract
The significant advances in the differentiation of human pluripotent stem (hPS) cells into pancreatic endocrine cells, including functional β-cells, have been based on a detailed understanding of the underlying developmental mechanisms. However, the final differentiation steps, leading from endocrine progenitors to mono-hormonal and mature pancreatic endocrine cells, remain to be fully understood and this is reflected in the remaining shortcomings of the hPS cell-derived islet cells (SC-islet cells), which include a lack of β-cell maturation and variability among different cell lines. Additional signals and modifications of the final differentiation steps will have to be assessed in a combinatorial manner to address the remaining issues and appropriate reporter lines would be useful in this undertaking. Here we report the generation and functional validation of hPS cell reporter lines that can monitor the generation of INS+ and GCG+ cells and their resolution into mono-hormonal cells (INSeGFP, INSeGFP/GCGmCHERRY) as well as β-cell maturation (INSeGFP/MAFAmCHERRY) and function (INSGCaMP6). The reporter hPS cell lines maintained strong and widespread expression of pluripotency markers and differentiated efficiently into definitive endoderm and pancreatic progenitor (PP) cells. PP cells from all lines differentiated efficiently into islet cell clusters that robustly expressed the corresponding reporters and contained glucose-responsive, insulin-producing cells. To demonstrate the applicability of these hPS cell reporter lines in a high-content live imaging approach for the identification of optimal differentiation conditions, we adapted our differentiation procedure to generate SC-islet clusters in microwells. This allowed the live confocal imaging of multiple SC-islets for a single condition and, using this approach, we found that the use of the N21 supplement in the last stage of the differentiation increased the number of monohormonal β-cells without affecting the number of α-cells in the SC-islets. The hPS cell reporter lines and the high-content live imaging approach described here will enable the efficient assessment of multiple conditions for the optimal differentiation and maturation of SC-islets.
Collapse
Affiliation(s)
- Elisa Zanfrini
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Manuj Bandral
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Luka Jarc
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Maria Alejandra Ramirez-Torres
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Daniela Pezzolla
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Center for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, TU Dresden, Dresden, Germany
| | - Vida Kufrin
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Eva Rodriguez-Aznar
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Ana Karen Mojica Avila
- Institute of Physiology, Faculty of Medicine, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Christian Cohrs
- Institute of Physiology, Faculty of Medicine, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Stephan Speier
- Institute of Physiology, Faculty of Medicine, TU Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany
| | - Katrin Neumann
- Stem Cell Engineering Facility (SCEF), CRTD, TU Dresden, Dresden, Germany
| | - Anthony Gavalas
- Paul Langerhans Institute Dresden (PLID) of Helmholtz Center Munich at the University Clinic Carl Gustav Carus of TU Dresden, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
- German Centre for Diabetes Research (DZD), Munich-Neuherberg, Germany.
| |
Collapse
|
|
9
|
Heyns IM, Arora M, Ganugula R, Allamreddy SR, Tiwari S, Shah DK, Basu R, Ravi Kumar MNV. Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein. ACS NANO 2024; 18:11863-11875. [PMID: 38622996 PMCID: PMC11145941 DOI: 10.1021/acsnano.4c01027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2024]
Abstract
Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro, ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo, as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro, ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.
Collapse
Affiliation(s)
- Ingrid Marie Heyns
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL 35401, United States
- Division of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL 35401, United States
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35401, United States
| | - Meenakshi Arora
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL 35401, United States
- Division of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL 35401, United States
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35401, United States
- Department of Biological Sciences, The University of Alabama, SEC 1325, Tuscaloosa, AL 35487, United States
| | - Raghu Ganugula
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL 35401, United States
- Division of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL 35401, United States
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35401, United States
- Department of Biological Sciences, The University of Alabama, SEC 1325, Tuscaloosa, AL 35487, United States
| | - Swetha Reddy Allamreddy
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL 35401, United States
- Division of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL 35401, United States
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35401, United States
| | - Shrusti Tiwari
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY 14214, United States
| | - Dhaval K. Shah
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY 14214, United States
| | - Rita Basu
- Division of Endocrinology, Diabetes, and Metabolism, School of Medicine, Marnix E. Heersink School of Medicine, The University of Alabama, Birmingham, AL 35294, United States
| | - M. N. V. Ravi Kumar
- The Center for Convergent Bioscience and Medicine (CCBM), The University of Alabama, Tuscaloosa, AL 35401, United States
- Division of Translational Science and Medicine, College of Community Health Sciences, The University of Alabama, Tuscaloosa, AL 35401, United States
- Alabama Life Research Institute, The University of Alabama, Tuscaloosa, AL 35401, United States
- Department of Biological Sciences, The University of Alabama, SEC 1325, Tuscaloosa, AL 35487, United States
- Chemical and Biological Engineering, University of Alabama, SEC 3448, Tuscaloosa, AL 35487, United States
- Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
- Nephrology Research and Training Center, Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, United States
| |
Collapse
|
|
10
|
Fabricius TW, Verhulst CEM, Kristensen PL, Holst JJ, Tack CJ, McCrimmon RJ, Heller SR, Evans ML, de Galan BE, Pedersen-Bjergaard U. Counterregulatory hormone and symptom responses to hypoglycaemia in people with type 1 diabetes, insulin-treated type 2 diabetes or without diabetes: the Hypo-RESOLVE hypoglycaemic clamp study. Acta Diabetol 2024; 61:623-633. [PMID: 38376580 PMCID: PMC11055751 DOI: 10.1007/s00592-024-02239-8] [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: 10/09/2023] [Accepted: 01/13/2024] [Indexed: 02/21/2024]
Abstract
AIM The sympathetic nervous and hormonal counterregulatory responses to hypoglycaemia differ between people with type 1 and type 2 diabetes and may change along the course of diabetes, but have not been directly compared. We aimed to compare counterregulatory hormone and symptom responses to hypoglycaemia between people with type 1 diabetes, insulin-treated type 2 diabetes and controls without diabetes, using a standardised hyperinsulinaemic-hypoglycaemic clamp. MATERIALS We included 47 people with type 1 diabetes, 15 with insulin-treated type 2 diabetes, and 32 controls without diabetes. Controls were matched according to age and sex to the people with type 1 diabetes or with type 2 diabetes. All participants underwent a hyperinsulinaemic-euglycaemic-(5.2 ± 0.4 mmol/L)-hypoglycaemic-(2.8 ± 0.13 mmol/L)-clamp. RESULTS The glucagon response was lower in people with type 1 diabetes (9.4 ± 0.8 pmol/L, 8.0 [7.0-10.0]) compared to type 2 diabetes (23.7 ± 3.7 pmol/L, 18.0 [12.0-28.0], p < 0.001) and controls (30.6 ± 4.7, 25.5 [17.8-35.8] pmol/L, p < 0.001). The adrenaline response was lower in type 1 diabetes (1.7 ± 0.2, 1.6 [1.3-5.2] nmol/L) compared to type 2 diabetes (3.4 ± 0.7, 2.6 [1.3-5.2] nmol/L, p = 0.001) and controls (2.7 ± 0.4, 2.8 [1.4-3.9] nmol/L, p = 0.012). Growth hormone was lower in people with type 2 diabetes than in type 1 diabetes, at baseline (3.4 ± 1.6 vs 7.7 ± 1.3 mU/L, p = 0.042) and during hypoglycaemia (24.7 ± 7.1 vs 62.4 ± 5.8 mU/L, p = 0.001). People with 1 diabetes had lower overall symptom responses than people with type 2 diabetes (45.3 ± 2.7 vs 58.7 ± 6.4, p = 0.018), driven by a lower neuroglycopenic score (27.4 ± 1.8 vs 36.7 ± 4.2, p = 0.012). CONCLUSION Acute counterregulatory hormone and symptom responses to experimental hypoglycaemia are lower in people with type 1 diabetes than in those with long-standing insulin-treated type 2 diabetes and controls.
Collapse
Affiliation(s)
- Therese W Fabricius
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark.
| | - Clementine E M Verhulst
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Peter L Kristensen
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Cees J Tack
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Rory J McCrimmon
- Systems Medicine, School of Medicine, University of Dundee, Dundee, UK
| | - Simon R Heller
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Mark L Evans
- Welcome MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Bastiaan E de Galan
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Internal Medicine, Maastricht UMC+, Maastricht, The Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, The Netherlands
| | - Ulrik Pedersen-Bjergaard
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
11
|
Uitbeijerse BS, Nijhoff MF, de Koning EJP. Comparison of an oral mixed meal plus arginine and intravenous glucose, GLP-1 plus arginine to unmask residual islet function in longstanding type 1 diabetes. Am J Physiol Endocrinol Metab 2024; 326:E673-E680. [PMID: 38446636 PMCID: PMC11376486 DOI: 10.1152/ajpendo.00030.2024] [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: 01/16/2024] [Revised: 02/27/2024] [Accepted: 02/27/2024] [Indexed: 03/08/2024]
Abstract
Residual beta cells are present in most patients with longstanding type 1 diabetes but it is unknown whether these beta cells react normally to different stimuli. Moreover a defect in proinsulin conversion and abnormal alpha cell response are also part of the islet dysfunction. A three-phase [euglycemia, hyperglycemia, and hyperglycemia + glucagon-like peptide 1 (GLP-1)] clamp was performed in patients with longstanding type 1 diabetes. Intravenous arginine boluses were administered at the end of each phase. On another day, a mixed meal stimulation test with a subsequent intravenous arginine bolus was performed. C-peptide was detectable in a subgroup of subjects at baseline (2/15) or only after stimulation (3/15). When detectable, C-peptide increased 2.9-fold [95% CI: 1.2-7.1] during the hyperglycemia phase and 14.1-fold [95% CI: 3.1-65.2] during the hyperglycemia + GLP-1 phase, and 22.3-fold [95% CI: 5.6-89.1] during hyperglycemia + GLP-1 + arginine phase when compared with baseline. The same subset of patients with a C-peptide response were identified during the mixed meal stimulation test as during the clamp. There was an inhibition of glucagon secretion (0.72-fold, [95% CI: 0.63-0.84]) during the glucose clamp irrespective of the presence of detectable beta cell function. Proinsulin was only present in a subset of subjects with detectable C-peptide (3/15) and proinsulin mimicked the C-peptide response to the different stimuli when detectable. Residual beta cells in longstanding type 1 diabetes respond adequately to different stimuli and could be of clinical benefit.NEW & NOTEWORTHY If beta cell function is detectable, the beta cells react relatively normal to the different stimuli except for the first phase response to intravenous glucose. An oral mixed meal followed by an intravenous arginine bolus can identify residual beta cell function/mass as well as the more commonly used glucose potentiated arginine-induced insulin secretion during a hyperglycemic clamp.
Collapse
Affiliation(s)
- Bas S Uitbeijerse
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Michiel F Nijhoff
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Eelco J P de Koning
- Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
|
12
|
Maguolo A, Mazzuca G, Smart CE, Maffeis C. Postprandial glucose metabolism in children and adolescents with type 1 diabetes mellitus: potential targets for improvement. Eur J Clin Nutr 2024; 78:79-86. [PMID: 37875611 DOI: 10.1038/s41430-023-01359-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/26/2023]
Abstract
The main goal of therapeutic management of type 1 Diabetes Mellitus (T1DM) is to maintain optimal glycemic control to prevent acute and long-term diabetes complications and to enable a good quality of life. Postprandial glycemia makes a substantial contribution to overall glycemic control and variability in diabetes and, despite technological advancements in insulin treatments, optimal postprandial glycemia is difficult to achieve. Several factors influence postprandial blood glucose levels in children and adolescents with T1DM, including nutritional habits and adjustment of insulin doses according to meal composition. Additionally, hormone secretion, enteroendocrine axis dysfunction, altered gastrointestinal digestion and absorption, and physical activity play important roles. Meal-time routines, intake of appropriate ratios of macronutrients, and correct adjustment of the insulin dose for the meal composition have positive impacts on postprandial glycemic variability and long-term cardiometabolic health of the individual with T1DM. Further knowledge in the field is necessary for management of all these factors to be part of routine pediatric diabetes education and clinical practice. Thus, the aim of this report is to review the main factors that influence postprandial blood glucose levels and metabolism, focusing on macronutrients and other nutritional and lifestyle factors, to suggest potential targets for improving postprandial glycemia in the management of children and adolescents with T1DM.
Collapse
Affiliation(s)
- Alice Maguolo
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy.
| | - Giorgia Mazzuca
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy
| | - Carmel E Smart
- School of Health Sciences, University of Newcastle, Callaghan, NSW, Australia
- Department of Paediatric Diabetes and Endocrinology, John Hunter Children's Hospital, Newcastle, NSW, Australia
| | - Claudio Maffeis
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Pediatrics, and Gynecology, University of Verona, Verona, Italy
| |
Collapse
|
|
13
|
Senthilkumaran M, Koch C, Herselman MF, Bobrovskaya L. Role of the Adrenal Medulla in Hypoglycaemia-Associated Autonomic Failure-A Diabetic Perspective. Metabolites 2024; 14:100. [PMID: 38392992 PMCID: PMC10890365 DOI: 10.3390/metabo14020100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
Hypoglycaemia-associated autonomic failure (HAAF) is characterised by an impairment in adrenal medullary and neurogenic symptom responses following episodes of recurrent hypoglycaemia. Here, we review the status quo of research related to the regulatory mechanisms of the adrenal medulla in its response to single and recurrent hypoglycaemia in both diabetic and non-diabetic subjects with particular focus given to catecholamine synthesis, enzymatic activity, and the impact of adrenal medullary peptides. Short-term post-transcriptional modifications, particularly phosphorylation at specific residues of tyrosine hydroxylase (TH), play a key role in the regulation of catecholamine synthesis. While the effects of recurrent hypoglycaemia on catecholamine synthetic enzymes remain inconsistent, long-term changes in TH protein expression suggest species-specific responses. Adrenomedullary peptides such as neuropeptide Y (NPY), galanin, and proenkephalin exhibit altered gene and protein expression in response to hypoglycaemia, suggesting a potential role in the modulation of catecholamine secretion. Of note is NPY, since its antagonism has been shown to prevent reductions in TH protein expression. This review highlights the need for further investigation into the molecular mechanisms involved in the adrenal medullary response to hypoglycaemia. Despite advancements in our understanding of HAAF in non-diabetic rodents, a reliable diabetic rodent model of HAAF remains a challenge.
Collapse
Affiliation(s)
- Manjula Senthilkumaran
- Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Coen Koch
- Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Mauritz Frederick Herselman
- Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Larisa Bobrovskaya
- Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| |
Collapse
|
|
14
|
Hoffman EG, D’Souza NC, Liggins RT, Riddell MC. Pharmacologic inhibition of somatostatin receptor 2 to restore glucagon counterregulation in diabetes. Front Pharmacol 2024; 14:1295639. [PMID: 38298268 PMCID: PMC10829877 DOI: 10.3389/fphar.2023.1295639] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 12/13/2023] [Indexed: 02/02/2024] Open
Abstract
Glucose homeostasis is primarily maintained by pancreatic hormones, insulin and glucagon, with an emerging role for a third islet hormone, somatostatin, in regulating insulin and glucagon responses. Under healthy conditions, somatostatin secreted from pancreatic islet δ-cells inhibits both insulin and glucagon release through somatostatin receptor- induced cAMP-mediated downregulation and paracrine inhibition of β- and α-cells, respectively. Since glucagon is the body's most important anti-hypoglycemic hormone, and because glucagon counterregulation to hypoglycemia is lost in diabetes, the study of somatostatin biology has led to new investigational medications now in development that may help to restore glucagon counterregulation in type 1 diabetes. This review highlights the normal regulatory role of pancreatic somatostatin signaling in healthy islet function and how the inhibition of somatostatin receptor signaling in pancreatic α-cells may restore normal glucagon counterregulation in diabetes mellitus.
Collapse
Affiliation(s)
- Emily G. Hoffman
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | - Ninoschka C. D’Souza
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| | | | - Michael C. Riddell
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, ON, Canada
| |
Collapse
|
|
15
|
Riddell MC, Gal RL, Bergford S, Patton SR, Clements MA, Calhoun P, Beaulieu LC, Sherr JL. The Acute Effects of Real-World Physical Activity on Glycemia in Adolescents With Type 1 Diabetes: The Type 1 Diabetes Exercise Initiative Pediatric (T1DEXIP) Study. Diabetes Care 2024; 47:132-139. [PMID: 37922335 DOI: 10.2337/dc23-1548] [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: 08/22/2023] [Accepted: 10/16/2023] [Indexed: 11/05/2023]
Abstract
OBJECTIVE Data from the Type 1 Diabetes Exercise Initiative Pediatric (T1DEXIP) study were evaluated to understand glucose changes during activity and identify factors that may influence changes. RESEARCH DESIGN AND METHODS In this real-world observational study, adolescents with type 1 diabetes self-reported physical activity, food intake, and insulin dosing (multiple-daily injection users) using a smartphone application. Heart rate and continuous glucose monitoring data were collected, as well as pump data downloads. RESULTS Two hundred fifty-one adolescents (age 14 ± 2 years [mean ± SD]; HbA1c 7.1 ± 1.3% [54 ± 14.2 mmol/mol]; 42% female) logged 3,738 activities over ∼10 days of observation. Preactivity glucose was 163 ± 66 mg/dL (9.1 ± 3.7 mmol/L), dropping to 148 ± 66 mg/dL (8.2 ± 3.7 mmol/L) by end of activity; median duration of activity was 40 min (20, 75 [interquartile range]) with a mean and peak heart rate of 109 ± 16 bpm and 130 ± 21 bpm. Drops in glucose were greater in those with lower baseline HbA1c levels (P = 0.002), shorter disease duration (P = 0.02), less hypoglycemia fear (P = 0.04), and a lower BMI (P = 0.05). Event-level predictors of greater drops in glucose included self-classified "noncompetitive" activities, insulin on board >0.05 units/kg body mass, glucose already dropping prior to the activity, preactivity glucose >150 mg/dL (>8.3 mmol/L) and time 70-180 mg/dL >70% in the 24 h before the activity (all P < 0.001). CONCLUSIONS Participant-level and activity event-level factors can help predict the magnitude of drop in glucose during real-world physical activity in youth with type 1 diabetes. A better appreciation of these factors may improve decision support tools and self-management strategies to reduce activity-induced dysglycemia in active adolescents living with the disease.
Collapse
Affiliation(s)
- Michael C Riddell
- School of Kinesiology and Health Science, Muscle Health Research Centre, York University, Toronto, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
16
|
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.
Collapse
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
| |
Collapse
|
|
17
|
Gaspari S, Labouèbe G, Picard A, Berney X, Rodriguez Sanchez‐Archidona A, Thorens B. Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia. EMBO Rep 2023; 24:e57344. [PMID: 37314252 PMCID: PMC10398655 DOI: 10.15252/embr.202357344] [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: 04/14/2023] [Revised: 05/21/2023] [Accepted: 05/31/2023] [Indexed: 06/15/2023] Open
Abstract
The counterregulatory response to hypoglycemia (CRR), which ensures a sufficient glucose supply to the brain, is an essential survival function. It is orchestrated by incompletely characterized glucose-sensing neurons, which trigger a coordinated autonomous and hormonal response that restores normoglycemia. Here, we investigate the role of hypothalamic Tmem117, identified in a genetic screen as a regulator of CRR. We show that Tmem117 is expressed in vasopressin magnocellular neurons of the hypothalamus. Tmem117 inactivation in these neurons increases hypoglycemia-induced vasopressin secretion leading to higher glucagon secretion in male mice, and this effect is estrus cycle phase dependent in female mice. Ex vivo electrophysiological analysis, in situ hybridization, and in vivo calcium imaging reveal that Tmem117 inactivation does not affect the glucose-sensing properties of vasopressin neurons but increases ER stress, ROS production, and intracellular calcium levels accompanied by increased vasopressin production and secretion. Thus, Tmem117 in vasopressin neurons is a physiological regulator of glucagon secretion, which highlights the role of these neurons in the coordinated response to hypoglycemia.
Collapse
Affiliation(s)
- Sevasti Gaspari
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| | - Gwenaël Labouèbe
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| | - Alexandre Picard
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| | - Xavier Berney
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| | | | - Bernard Thorens
- Center for Integrative GenomicsUniversity of LausanneLausanneSwitzerland
| |
Collapse
|
|
18
|
Warner SO, Dai Y, Sheanon N, Yao MV, Cason RL, Arbabi S, Patel SB, Lindquist D, Winnick JJ. Short-term fasting lowers glucagon levels under euglycemic and hypoglycemic conditions in healthy humans. JCI Insight 2023; 8:e169789. [PMID: 37166980 PMCID: PMC10371233 DOI: 10.1172/jci.insight.169789] [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: 02/15/2023] [Accepted: 05/09/2023] [Indexed: 05/12/2023] Open
Abstract
Fasting is associated with increased susceptibility to hypoglycemia in people with type 1 diabetes, thereby making it a significant health risk. To date, the relationship between fasting and insulin-induced hypoglycemia has not been well characterized, so our objective was to determine whether insulin-independent factors, such as counterregulatory hormone responses, are adversely impacted by fasting in healthy control individuals. Counterregulatory responses to insulin-induced hypoglycemia were measured in 12 healthy people during 2 metabolic studies. During one study, participants ate breakfast and lunch, after which they underwent a 2-hour bout of insulin-induced hypoglycemia (FED). During the other study, participants remained fasted prior to hypoglycemia (FAST). As expected, hepatic glycogen concentrations were lower in FAST, and associated with diminished peak glucagon levels and reduced endogenous glucose production (EGP) during hypoglycemia. Accompanying lower EGP in FAST was a reduction in peripheral glucose utilization, and a resultant reduction in the amount of exogenous glucose required to maintain glycemia. These data suggest that whereas a fasting-induced lowering of glucose utilization could potentially delay the onset of insulin-induced hypoglycemia, subsequent reductions in glucagon levels and EGP are likely to encumber recovery from it. As a result of this diminished metabolic flexibility in response to fasting, susceptibility to hypoglycemia could be enhanced in patients with type 1 diabetes under similar conditions.
Collapse
Affiliation(s)
- Shana O. Warner
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Yufei Dai
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Nicole Sheanon
- Department of Pediatrics, Division of Pediatric Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Michael V. Yao
- Department of Pediatrics, Division of Endocrinology, University of New Mexico, Albuquerque, New Mexico, USA
| | - Rebecca L. Cason
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Shahriar Arbabi
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Shailendra B. Patel
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Diana Lindquist
- Imaging Research Center, Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jason J. Winnick
- Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
|
19
|
Infante M, Ricordi C. The unique pathophysiological features of diabetes mellitus secondary to total pancreatectomy: proposal for a new classification distinct from diabetes of the exocrine pancreas. Expert Rev Endocrinol Metab 2023; 18:19-32. [PMID: 36692892 DOI: 10.1080/17446651.2023.2168645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 01/11/2023] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM). AREAS COVERED TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes ('brittle diabetes'). EXPERT OPINION We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.
Collapse
Affiliation(s)
- Marco Infante
- Cell Transplant Center, Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
- Section of Diabetes and Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy
- Diabetes Research Institute Federation (DRIF), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
20
|
Story LH, Wilson LM. New Developments in Glucagon Treatment for Hypoglycemia. Drugs 2022; 82:1179-1191. [PMID: 35932416 DOI: 10.1007/s40265-022-01754-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2022] [Indexed: 11/28/2022]
Abstract
Glucagon is essential for endogenous glucose regulation along with the paired hormone, insulin. Unlike insulin, pharmaceutical use of glucagon has been limited due to the unstable nature of the peptide. Glucagon has the potential to address hypoglycemia as a major limiting factor in the treatment of diabetes, which remains very common in the type 1 and type 2 diabetes. Recent developments are poised to change this paradigm and expand the use of glucagon for people with diabetes. Glucagon emergency kits have major limitations for their use in treating severe hypoglycemia. A complicated reconstitution and injection process often results in incomplete or aborted administration. New preparations include intranasal glucagon with an easy-to-use and needle-free nasal applicator as well as two stable liquid formulations in pre-filled injection devices. These may ease the burden of severe hypoglycemia treatment. The liquid preparations may also have a role in the treatment of non-severe hypoglycemia. Despite potential benefits of expanded use of glucagon, undesirable side effects (nausea, vomiting), cost, and complexity of adding another medication may limit real-world use. Additionally, more long-term safety and outcome data are needed before widespread, frequent use of glucagon is recommended by providers.
Collapse
Affiliation(s)
- LesleAnn Hayward Story
- Division of Endocrinology, Harold Schnitzer Diabetes Health Center, Oregon Health & Science University, Portland, OR, USA
| | - Leah M Wilson
- Division of Endocrinology, Harold Schnitzer Diabetes Health Center, Oregon Health & Science University, Portland, OR, USA.
| |
Collapse
|
|
21
|
Colberg SR. Why Glucagon Matters for Hypoglycemia and Physical Activity in Individuals With Type 1 Diabetes. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2022; 3:889248. [PMID: 36992764 PMCID: PMC10012082 DOI: 10.3389/fcdhc.2022.889248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/15/2022] [Indexed: 11/13/2022]
|
|
22
|
Verberne AJM, Mussa BM. Neural control of pancreatic peptide hormone secretion. Peptides 2022; 152:170768. [PMID: 35189258 DOI: 10.1016/j.peptides.2022.170768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/10/2022] [Accepted: 02/12/2022] [Indexed: 11/20/2022]
Abstract
Pancreatic peptide hormone secretion is inextricably linked to maintenance of normal levels of blood glucose. In animals and man, pancreatic peptide hormone secretion is controlled, at least in part, by input from parasympathetic (vagal) premotor neurons that are found principally in the dorsal motor nucleus of the vagus (DMV). Iatrogenic (insulin-induced) hypoglycaemia evokes a homeostatic response commonly referred to as the glucose counter-regulatory response. This homeostatic response is of particular importance in Type 1 diabetes in which episodes of hypoglycaemia are common, debilitating and lead to suboptimal control of blood glucose. Glucagon is the principal counterregulatory hormone but for reasons unknown, its secretion during insulin-induced hypoglycaemia is impaired. Pancreatic parasympathetic neurons are distinguishable electrophysiologically from those that control other (e.g. gastric) functions and are controlled by supramedullary inputs from hypothalamic structures such as the perifornical region. During hypoglycaemia, glucose-sensitive, GABAergic neurons in the ventromedial hypothalamus are inhibited leading to disinhibition of perifornical orexin neurons with projections to the DMV which, in turn, leads to increased secretion of glucagon.
Collapse
Affiliation(s)
- Anthony J M Verberne
- Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria 3084, Australia.
| | - Bashair M Mussa
- Basic Medical Science Department, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates
| |
Collapse
|
|
23
|
Cabral MD, Patel DR, Greydanus DE, Deleon J, Hudson E, Darweesh S. Medical perspectives on pediatric sports medicine–Selective topics. Dis Mon 2022; 68:101327. [DOI: 10.1016/j.disamonth.2022.101327] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
24
|
Brawerman G, Ntranos V, Thompson PJ. Alpha cell dysfunction in type 1 diabetes is independent of a senescence program. Front Endocrinol (Lausanne) 2022; 13:932516. [PMID: 36277717 PMCID: PMC9586489 DOI: 10.3389/fendo.2022.932516] [Citation(s) in RCA: 12] [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: 04/29/2022] [Accepted: 09/20/2022] [Indexed: 11/13/2022] Open
Abstract
Type 1 Diabetes (T1D) is caused by insulin deficiency, due to progressive autoimmune destruction of pancreatic β cells. Glucagon-secreting α cells become dysfunctional in T1D and contribute to pathophysiology, however, the mechanisms involved are unclear. While the majority of β cells are destroyed in T1D, some β cells escape this fate and become senescent but whether α cell dysfunction involves a senescence program has not been explored. Here we addressed the question of whether α cells become senescent during the natural history of T1D in the non-obese diabetic (NOD) mouse model and humans. NOD mice had several distinct subpopulations of α cells, but none were defined by markers of senescence at the transcriptional or protein level. Similarly, α cells of human T1D donors did not express senescence markers. Despite the lack of senescence in α cells in vivo, using a human islet culture model, we observed that DNA damage-induced senescence led to alterations in islet glucagon secretion, which could be rescued by inhibiting the senescence-associated secretory phenotype (SASP). Together our results suggest that α cell dysfunction in T1D is not due to activation of a senescence program, however, senescent β cell accumulation in the islet microenvironment may have a negative effect on α cell function.
Collapse
Affiliation(s)
- Gabriel Brawerman
- Department of Physiology & Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) theme, Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Vasilis Ntranos
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
- Diabetes Center, University of California San Francisco, San Francisco, CA, United States
| | - Peter J. Thompson
- Department of Physiology & Pathophysiology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) theme, Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
- *Correspondence: Peter J. Thompson,
| |
Collapse
|
|
25
|
Kim A, Knudsen JG, Madara JC, Benrick A, Hill TG, Abdul Kadir L, Kellard JA, Mellander L, Miranda C, Lin H, James T, Suba K, Spigelman AF, Wu Y, MacDonald PE, Wernstedt Asterholm I, Magnussen T, Christensen M, Vilsbøll T, Salem V, Knop FK, Rorsman P, Lowell BB, Briant LJB. Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes. eLife 2021; 10:e72919. [PMID: 34787082 PMCID: PMC8654374 DOI: 10.7554/elife.72919] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/16/2021] [Indexed: 01/27/2023] Open
Abstract
Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.
Collapse
Affiliation(s)
- Angela Kim
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Program in Neuroscience, Harvard Medical SchoolBostonUnited States
| | - Jakob G Knudsen
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Section for Cell Biology and Physiology, Department of Biology, University of CopenhagenCopenhagenDenmark
| | - Joseph C Madara
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
| | - Anna Benrick
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Thomas G Hill
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Lina Abdul Kadir
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Joely A Kellard
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Lisa Mellander
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Caroline Miranda
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Haopeng Lin
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Timothy James
- Department of Clinical Biochemistry, John Radcliffe, Oxford NHS TrustOxfordUnited Kingdom
| | - Kinga Suba
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College LondonLondonUnited Kingdom
| | - Aliya F Spigelman
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Yanling Wu
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Patrick E MacDonald
- Alberta Diabetes Institute, Li Ka Shing Centre for Health Research InnovationEdmontonCanada
| | - Ingrid Wernstedt Asterholm
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Tore Magnussen
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
| | - Mikkel Christensen
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagenDenmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenCopenhagenDenmark
| | - Victoria Salem
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College LondonLondonUnited Kingdom
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte HospitalHellerupDenmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of CopenhagenCopenhagenDenmark
- Steno Diabetes Center CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of CopenhagenCopenhagenDenmark
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Metabolic Research Unit, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of GothenburgGöteborgSweden
| | - Bradford B Lowell
- Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical CenterBostonUnited States
- Program in Neuroscience, Harvard Medical SchoolBostonUnited States
| | - Linford JB Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of OxfordOxfordUnited Kingdom
- Department of Computer Science, University of OxfordOxfordUnited Kingdom
| |
Collapse
|
|
26
|
Infante M, Baidal DA, Rickels MR, Fabbri A, Skyler JS, Alejandro R, Ricordi C. Dual-hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions. Artif Organs 2021; 45:968-986. [PMID: 34263961 PMCID: PMC9059950 DOI: 10.1111/aor.14023] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/09/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023]
Abstract
Over the last few years, technological advances have led to tremendous improvement in the management of type 1 diabetes (T1D). Artificial pancreas systems have been shown to improve glucose control compared with conventional insulin pump therapy. However, clinically significant hypoglycemic and hyperglycemic episodes still occur with the artificial pancreas. Postprandial glucose excursions and exercise-induced hypoglycemia represent major hurdles in improving glucose control and glucose variability in many patients with T1D. In this regard, dual-hormone artificial pancreas systems delivering other hormones in addition to insulin (glucagon or amylin) may better reproduce the physiology of the endocrine pancreas and have been suggested as an alternative tool to overcome these limitations in clinical practice. In addition, novel ultra-rapid-acting insulin analogs with a more physiological time-action profile are currently under investigation for use in artificial pancreas devices, aiming to address the unmet need for further improvements in postprandial glucose control. This review article aims to discuss the current progress and future outlook in the development of novel ultra-rapid insulin analogs and dual-hormone closed-loop systems, which offer the next steps to fully closing the loop in the artificial pancreas.
Collapse
Affiliation(s)
- Marco Infante
- Clinical Cell Transplant Program, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Division of Endocrinology, Metabolism and Diabetes, Department of Systems Medicine, CTO A. Alesini Hospital, Diabetes Research Institute Federation, University of Rome Tor Vergata, Rome, Italy
- UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy
| | - David A. Baidal
- Clinical Cell Transplant Program, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Michael R. Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Andrea Fabbri
- Division of Endocrinology, Metabolism and Diabetes, Department of Systems Medicine, CTO A. Alesini Hospital, Diabetes Research Institute Federation, University of Rome Tor Vergata, Rome, Italy
| | - Jay S. Skyler
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Rodolfo Alejandro
- Clinical Cell Transplant Program, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Camillo Ricordi
- Clinical Cell Transplant Program, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
27
|
Bisgaard Bengtsen M, Møller N. Mini-review: Glucagon responses in type 1 diabetes - a matter of complexity. Physiol Rep 2021; 9:e15009. [PMID: 34405569 PMCID: PMC8371343 DOI: 10.14814/phy2.15009] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
In recent years the role of altered alpha cell function and glucagon secretion in type 1 diabetes has attracted scientific attention. It is well established that glucagon responses to hypoglycemia are absent in type 1 diabetes, but more uncertain whether it is intact following other physiological and metabolic stimuli compared with nondiabetic individuals. The aim of this review is to (i) summarize current knowledge on glucagon responses during hypoglycemia in normal physiology and type 1 diabetes, and (ii) review human in vivo studies investigating glucagon responses after other stimuli in individuals with type 1 diabetes and nondiabetic individuals. Available data suggest that in type 1 diabetes the absence of glucagon secretion after hypoglycemia is irreversible. This is a scenario specific to hypoglycemia, since other stimuli, including administration of amino acids, insulin withdrawal, lipopolysaccharide exposure and exercise lead to substantial glucagon responses though attenuated compared to nondiabetic individuals in head-to-head studies. The derailed glucagon secretion is not confined to hypoglycemia as individuals with type 1 diabetes, as opposed to nondiabetic individuals display glucagon hypersecretion after meals, thereby potentially contributing to insulin resistance. The complexity of these phenomena may relate to activation of distinct regulatory pathways controlling glucagon secretion i.e., intra-islet paracrine signaling, direct and autonomic nervous signaling.
Collapse
Affiliation(s)
- Mads Bisgaard Bengtsen
- Department of Endocrinology and Internal MedicineAarhus University HospitalAarhusDenmark
- Department of Internal MedicineRegional Hospital HorsensHorsensDenmark
| | - Niels Møller
- Department of Endocrinology and Internal MedicineAarhus University HospitalAarhusDenmark
| |
Collapse
|
|
28
|
Burckhardt MA, Abraham MB, Dart J, Smith GJ, Paramalingam N, O'Dea J, de Bock M, Davis EA, Jones TW. Impact of Hybrid Closed Loop Therapy on Hypoglycemia Awareness in Individuals with Type 1 Diabetes and Impaired Hypoglycemia Awareness. Diabetes Technol Ther 2021; 23:482-490. [PMID: 33555982 DOI: 10.1089/dia.2020.0593] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Objective: This study evaluated the efficacy of using a hybrid closed loop (HCL) system in restoring hypoglycemia awareness in individuals with impaired awareness of hypoglycemia (IAH). Research Design and Methods: Participants with IAH (Gold score ≥4) were recruited into a randomized crossover pilot study. They participated in two 8-week periods using a HCL system (Medtronic 670G™) (intervention) and standard insulin pump therapy (control). Hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of each study period for the evaluation of the counter-regulatory hormonal and symptomatic responses to hypoglycemia. Results: Seventeen participants (mean age [standard deviation] 35.8 years [11.2 years]) were included in the study. Peak epinephrine levels (median, interquartile range [IQR]) in response to hypoglycemia were similar postintervention and control periods; 234.7 pmol/L (109.2; 938.9) versus 188.3 pmol/L (133.7; 402.9), P = 0.233. However, both peak adrenergic and neuroglycopenic symptom scores were higher after intervention; 5.0 (4.5; 9.0) versus 4.0 (4.0; 5.5), P = 0.009, and 8.5 (6.0; 15.0) versus 6.5 (6.0; 7.0) P = 0.014, respectively. Self-reported hypoglycemia awareness improved: median (IQR) Gold score was 4.0 (3.0; 5.5) versus 5.5 (4.5; 6.0); intervention versus control, P = 0.033. Time spent <3.9 and <3.0 mmol/L was lower in the intervention group than in control, P = 0.002. Other patient-reported outcomes (hypoglycemia fear and diabetes treatment satisfaction) did not change. Conclusions: A short-term use of a HCL system failed to demonstrate an improvement in counter-regulatory hormonal responses. However, higher hypoglycemia symptom scores during controlled hypoglycemia, better self-reported hypoglycemia awareness, and less time spent in hypoglycemia suggest the potential benefits of a HCL system in people with IAH. Trial Registration: anzctr.org.au Identifier: ACTRN12616000909426.
Collapse
Affiliation(s)
- Marie-Anne Burckhardt
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Mary B Abraham
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Julie Dart
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
| | - Grant J Smith
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Nirubasini Paramalingam
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Joanne O'Dea
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Martin de Bock
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Elizabeth A Davis
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| | - Timothy W Jones
- Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia
- Division of Paediatrics, Medical School, The University of Western Australia, Perth, Western Australia, Australia
| |
Collapse
|
|
29
|
Moore MC, Warner SO, Dai Y, Sheanon N, Smith M, Farmer B, Cason RL, Cherrington AD, Winnick JJ. C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions. JCI Insight 2021; 6:148997. [PMID: 34003799 PMCID: PMC8262495 DOI: 10.1172/jci.insight.148997] [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] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 05/12/2021] [Indexed: 12/17/2022] Open
Abstract
Several studies have associated the presence of residual insulin secretion capability (also referred to as being C-peptide positive) with lower risk of insulin-induced hypoglycemia in patients with type 1 diabetes (T1D), although the reason is unclear. We tested the hypothesis that C-peptide infusion would enhance glucagon secretion in response to hyperinsulinemia during euglycemic and hypoglycemic conditions in dogs (5 male/4 female). After a 2-hour basal period, an intravenous (IV) infusion of insulin was started, and dextrose was infused to maintain euglycemia for 2 hours. At the same time, an IV infusion of either saline (SAL) or C-peptide (CPEP) was started. After this euglycemic period, the insulin and SAL/CPEP infusions were continued for another 2 hours, but the glucose was allowed to fall to approximately 50 mg/dL. In response to euglycemic-hyperinsulinemia, glucagon secretion decreased in SAL but remained unchanged from the basal period in CPEP condition. During hypoglycemia, glucagon secretion in CPEP was 2 times higher than SAL, and this increased net hepatic glucose output and reduced the amount of exogenous glucose required to maintain glycemia. These data suggest that the presence of C-peptide during IV insulin infusion can preserve glucagon secretion during euglycemia and enhance it during hypoglycemia, which could explain why T1D patients with residual insulin secretion are less susceptible to hypoglycemia.
Collapse
Affiliation(s)
- Mary Courtney Moore
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Shana O. Warner
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Yufei Dai
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Nicole Sheanon
- Department of Endocrinology, University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Marta Smith
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Ben Farmer
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Rebecca L. Cason
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Alan D. Cherrington
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Jason J. Winnick
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| |
Collapse
|
|
30
|
Wszoła M, Nitarska D, Cywoniuk P, Gomółka M, Klak M. Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes. Cells 2021; 10:1544. [PMID: 34207441 PMCID: PMC8234129 DOI: 10.3390/cells10061544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Often, intensive insulin therapy is insufficient, and patients require a pancreas or pancreatic islets transplant. However, both solutions are associated with many possible complications, including graft rejection. The best approach seems to be a donor-independent T1D treatment strategy based on human stem cells cultured in vitro and differentiated into insulin and glucagon-producing cells (β and α cells, respectively). Both types of cells can then be incorporated into the bio-ink used for 3D printing of the bionic pancreas, which can be transplanted into T1D patients to restore glucose homeostasis. The aim of this review is to summarize current knowledge about stem cells sources and their transformation into key pancreatic cells. Last, but not least, we comment on possible solutions of post-transplant immune response triggered stem cell-derived pancreatic cells and their potential control mechanisms.
Collapse
Affiliation(s)
- Michał Wszoła
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
- Polbionica Ltd., 01-793 Warsaw, Poland;
- Medispace Medical Centre, 01-044 Warsaw, Poland
| | | | - Piotr Cywoniuk
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
| | - Magdalena Gomółka
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
| | - Marta Klak
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
- Polbionica Ltd., 01-793 Warsaw, Poland;
| |
Collapse
|
|
31
|
Bagger JI, Grøndahl MFG, Lund A, Holst JJ, Vilsbøll T, Knop FK. Glucagonostatic Potency of GLP-1 in Patients With Type 2 Diabetes, Patients With Type 1 Diabetes, and Healthy Control Subjects. Diabetes 2021; 70:1347-1356. [PMID: 33722838 DOI: 10.2337/db20-0998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 03/03/2021] [Indexed: 11/13/2022]
Abstract
Hyperglucagonemia is a well-known contributor to diabetic hyperglycemia, and glucagon-like peptide 1 (GLP-1) suppresses glucagon secretion. Reduced inhibitory effects of glucose and GLP-1 on glucagon secretion may contribute to the hyperglucagonemia in diabetes and influence the success of GLP-1 receptor agonist therapy. We examined the dose-response relationship for GLP-1 on glucose-induced glucagon suppression in healthy individuals and patients with type 2 and type 1 diabetes. In randomized order, 10 healthy individuals with normal glucose tolerance, 10 patients with type 2 diabetes, and 9 C-peptide-negative patients with type 1 diabetes underwent 4 separate stepwise glucose clamps (five 30-min steps from fasting level to 15 mmol/L plasma glucose) during simultaneous intravenous infusions of saline or 0.2, 0.4, or 0.8 pmol GLP-1/kg/min. In healthy individuals and patients with type 2 diabetes, GLP-1 potentiated the glucagon-suppressive effect of intravenous glucose in a dose-dependent manner. In patients with type 1 diabetes, no significant changes in glucagon secretion were observed during the clamps whether with saline or GLP-1 infusions. In conclusion, the glucagonostatic potency of GLP-1 during a stepwise glucose clamp is preserved in patients with type 2 diabetes, whereas our patients with type 1 diabetes were insensitive to the glucagonostatic effects of both glucose and GLP-1.
Collapse
Affiliation(s)
- Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Magnus F G Grøndahl
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Asger Lund
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
32
|
Warner SO, Wadian AM, Smith M, Farmer B, Dai Y, Sheanon N, Edgerton DS, Winnick JJ. Liver glycogen-induced enhancements in hypoglycemic counterregulation require neuroglucopenia. Am J Physiol Endocrinol Metab 2021; 320:E914-E924. [PMID: 33779306 PMCID: PMC8424545 DOI: 10.1152/ajpendo.00501.2020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 03/24/2021] [Accepted: 03/24/2021] [Indexed: 01/24/2023]
Abstract
Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; n = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; n = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; n = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain.NEW & NOTEWORTHY It is well known that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in patients with diabetes. Our data confirm that increasing liver glycogen content 75% above fasting levels enhances hormonal responses to insulin-induced hypoglycemia and demonstrate that this enhanced hormonal response does not occur in the absence of hypoglycemia in the brain. These data demonstrate that information from the liver regarding glycogen availability is integrated in the brain to optimize the counterregulatory response.
Collapse
Affiliation(s)
- Shana O Warner
- Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Abby M Wadian
- Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Marta Smith
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ben Farmer
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Yufei Dai
- Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Nicole Sheanon
- Department of Endocrinology, University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Dale S Edgerton
- Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jason J Winnick
- Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio
| |
Collapse
|
|
33
|
Laugesen C, Schmidt S, Holst JJ, Nørgaard K, Ranjan AG. The effect of preceding glucose decline rate on low-dose glucagon efficacy in individuals with type 1 diabetes: A randomized crossover trial. Diabetes Obes Metab 2021; 23:1057-1062. [PMID: 33336888 DOI: 10.1111/dom.14301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/04/2020] [Accepted: 12/13/2020] [Indexed: 11/30/2022]
Abstract
Identifying determinants of low-dose glucagon efficacy is important to optimise its utilization for prevention and treatment of hypoglycaemia in individuals with type 1 diabetes. The study objective was to investigate whether the preceding glucose decline rate affects glucose response to low-dose glucagon administration. Ten adults with insulin pump-treated type 1 diabetes were included in this randomized, single-blind, two-way crossover study. Using a hyperinsulinaemic clamp technique, plasma glucose levels were reduced with either a rapid or slow decline rate while maintaining fixed insulin levels. When the plasma glucose level reached 3.9 mmoL/L, insulin and glucose infusions were discontinued and 150 μg subcutaneous glucagon was administered, followed by 120 minutes of plasma glucose monitoring. The positive incremental area under the glucose curve after administration of low-dose glucagon did not differ between the rapid-decline and slow-decline visits (mean ± SEM: 220 ± 49 vs. 174 ± 31 mmoL/L x min; P = 0.21). Similarly, no differences in total area under the glucose curve, peak plasma glucose, incremental peak plasma glucose, time-to-peak plasma glucose or end plasma glucose were observed. Thus, preceding glucose decline rate did not significantly affect the glucose response to low-dose glucagon.
Collapse
Affiliation(s)
| | - Signe Schmidt
- Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Jens Juul Holst
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kirsten Nørgaard
- Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Ajenthen G Ranjan
- Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Danish Diabetes Academy, Odense, Denmark
| |
Collapse
|
|
34
|
Lyhne MK, Vegge A, Povlsen GK, Slaaby R, Kildegaard J, Pedersen-Bjergaard U, Olsen LH. Hyperinsulinaemic hypoglycaemia in non-anaesthetized Göttingen minipigs induces a counter-regulatory endocrine response and electrocardiographic changes. Sci Rep 2021; 11:5983. [PMID: 33727615 PMCID: PMC7966749 DOI: 10.1038/s41598-021-84758-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/12/2021] [Indexed: 12/18/2022] Open
Abstract
The potentially fatal cardiovascular effects of hypoglycaemia are not well understood and large animal models of the counter-regulatory responses and cardiovascular consequences of insulin-induced hypoglycaemia are needed to understand the mechanisms in humans. The aim of this study was to develop a human-like minipig model of hypoglycaemia including healthy and diabetic pigs to investigate endocrine, electrocardiographic and platelet effects. Hypoglycaemia was induced using a hyperinsulinaemic, hypoglycaemic clamp and an insulin bolus protocol. Plasma glucose, glucagon, C-peptide, insulin, epinephrine and platelet aggregation responses were measured before, during and after hypoglycaemia. Continuous electrocardiographic recordings were obtained. Hypoglycaemia at a plasma glucose concentration of 0.8–1.0 mM in the clamp induced 25-fold increase in epinephrine and sixfold and threefold increase in glucagon for healthy and diabetic pigs, respectively. The hypoglycaemic clamp induced QTc-interval prolongation and increase in cardiac arrhythmias. In the bolus approach, the non-diabetic group reached plasma glucose target of 1.5 mM and QTc-interval was prolonged after insulin injection, but before glucose nadir. The diabetic group did not reach hypoglycaemic target, but still demonstrated QTc-interval prolongation. These results demonstrate effects of hyperinsulinaemic hypoglycaemia closely resembling human physiology, indicating the minipig as a translational animal model of counter-regulatory endocrine and myocardial effects of hypoglycaemia.
Collapse
Affiliation(s)
- Mille K Lyhne
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Andreas Vegge
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | - Rita Slaaby
- Global Drug Discovery, Novo Nordisk A/S, Måløv, Denmark
| | | | | | - Lisbeth H Olsen
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
35
|
Akinci G, Savelieff MG, Gallagher G, Callaghan BC, Feldman EL. Diabetic neuropathy in children and youth: New and emerging risk factors. Pediatr Diabetes 2021; 22:132-147. [PMID: 33205601 PMCID: PMC11533219 DOI: 10.1111/pedi.13153] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/02/2020] [Accepted: 11/12/2020] [Indexed: 12/23/2022] Open
Abstract
Pediatric neuropathy attributed to metabolic dysfunction is a well-known complication in children and youth with type 1 diabetes. Moreover, the rise of obesity and in particular of type 2 diabetes may cause an uptick in pediatric neuropathy incidence. However, despite the anticipated increase in neuropathy incidence, pathogenic insights and strategies to prevent or manage neuropathy in the setting of diabetes and obesity in children and youth remain unknown. Data from adult studies and available youth cohort studies are providing an initial understanding of potential diagnostic, management, and preventative measures in early life. This review discusses the current state of knowledge emanating from these efforts, with particular emphasis on the prevalence, clinical presentation, diagnostic approaches and considerations, and risk factors of neuropathy in type 1 and type 2 diabetes in children and youth. Also highlighted are current management strategies and recommendations for neuropathy in children and youth with diabetes. This knowledge, along with continued and sustained emphasis on identifying and eliminating modifiable risk factors, completing randomized controlled trials to assess effectiveness of strategies like weight loss and exercise, and enhancing awareness to support early detection and prevention, are pertinent to addressing the rising incidence of neuropathy associated with diabetes and obesity in children and youth.
Collapse
Affiliation(s)
- Gulcin Akinci
- Department of Neurology, University of Michigan Medicine, Ann Arbor, MI
| | | | - Gary Gallagher
- Department of Neurology, University of Michigan Medicine, Ann Arbor, MI
| | | | - Eva L. Feldman
- Department of Neurology, University of Michigan Medicine, Ann Arbor, MI
| |
Collapse
|
|
36
|
Flatt AJS, Greenbaum CJ, Shaw JAM, Rickels MR. Pancreatic islet reserve in type 1 diabetes. Ann N Y Acad Sci 2021; 1495:40-54. [PMID: 33550589 DOI: 10.1111/nyas.14572] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/18/2021] [Accepted: 01/21/2021] [Indexed: 12/22/2022]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet β cell loss and dysfunction resulting in insulin deficiency and hyperglycemia. During a presymptomatic phase of established β cell autoimmunity, β cell loss may first be evident through assessment of β cell secretory capacity, a measure of functional β cell mass. Reduction in pancreatic islet β cell reserve eventually manifests as impaired first-phase insulin response to glucose and abnormal glucose tolerance, which progresses until the functional capacity for β cell secretion can no longer meet the demand for insulin to control glycemia. A functional β cell mass of ∼25% of normal may be required to avoid symptomatic T1D but is already associated with dysregulated glucagon secretion. With symptomatic T1D, stimulated C-peptide levels >0.60 ng/mL (0.200 pmol/mL) indicate the presence of clinically meaningful residual β cell function for contributing to glycemic control, although even higher residual C-peptide appears necessary for evidencing glucose-dependent islet β and α cell function that may contribute to maintaining (near)normal glycemia. β cell replacement by islet transplantation can restore a physiologic reserve capacity for insulin secretion, confirming thresholds for functional β cell mass required for independence from insulin therapy.
Collapse
Affiliation(s)
- Anneliese J S Flatt
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - Carla J Greenbaum
- Diabetes Program and Center for Interventional Immunology, Benaroya Research Institute, Seattle, Washington
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.,Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK
| | - Michael R Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.,Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
| |
Collapse
|
|
37
|
Ergun-Longmire B, Clemente E, Vining-Maravolo P, Roberts C, Buth K, Greydanus DE. Diabetes education in pediatrics: How to survive diabetes. Dis Mon 2021; 67:101153. [PMID: 33541707 DOI: 10.1016/j.disamonth.2021.101153] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is the most common abnormal carbohydrate metabolism disorder affecting millions of people worldwide. It is characterized by hyperglycemia as a result of ß-cell destruction or dysfunction by both genetic and environmental factors. Over time chronic hyperglycemia leads to microvascular (i.e., retinopathy, nephropathy and neuropathy) and macrovascular (i.e., ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) complications of diabetes. Diabetes complication trials showed the importance of achieving near-normal glycemic control to prevent and/or reduce diabetes-related morbidity and mortality. There is a staggering rate of increased incidence of diabetes in youth, raising concerns for future generations' health, quality of life and its enormous economic burden. Despite advancements in the technology, diabetes management remains cumbersome. Training individuals with diabetes to gain life-long survival skills requires a comprehensive and ongoing diabetes education by a multidisciplinary team. Diabetes education and training start at the time of diagnosis of diabetes and should be continuous throughout the course of disease. The goal is to empower the individuals and families to gain diabetes self-management skills. Diabetes education must be individualized depending on the individual's age, education, family dynamics, and support. In this article, we review the history of diabetes, etiopathogenesis and clinical presentation of both type 1 and type 2 diabetes in children as well as adolescents. We then focus on diabetes management with education methods and materials.
Collapse
Affiliation(s)
- Berrin Ergun-Longmire
- Associate Professor, Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA.
| | - Ethel Clemente
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Patricia Vining-Maravolo
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Cheryl Roberts
- Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Koby Buth
- Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
| | - Donald E Greydanus
- Professor, Department of Pediatric and Adolescent Medicine, Western Michigan University, Homer Stryker M.D. School of Medicine, Kalamazoo, MI United States
| |
Collapse
|
|
38
|
Bourgeois S, Sawatani T, Van Mulders A, De Leu N, Heremans Y, Heimberg H, Cnop M, Staels W. Towards a Functional Cure for Diabetes Using Stem Cell-Derived Beta Cells: Are We There Yet? Cells 2021; 10:cells10010191. [PMID: 33477961 PMCID: PMC7835995 DOI: 10.3390/cells10010191] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a pandemic metabolic disorder that results from either the autoimmune destruction or the dysfunction of insulin-producing pancreatic beta cells. A promising cure is beta cell replacement through the transplantation of islets of Langerhans. However, donor shortage hinders the widespread implementation of this therapy. Human pluripotent stem cells, including embryonic stem cells and induced pluripotent stem cells, represent an attractive alternative beta cell source for transplantation. Although major advances over the past two decades have led to the generation of stem cell-derived beta-like cells that share many features with genuine beta cells, producing fully mature beta cells remains challenging. Here, we review the current status of beta cell differentiation protocols and highlight specific challenges that are associated with producing mature beta cells. We address the challenges and opportunities that are offered by monogenic forms of diabetes. Finally, we discuss the remaining hurdles for clinical application of stem cell-derived beta cells and the status of ongoing clinical trials.
Collapse
Affiliation(s)
- Stephanie Bourgeois
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Toshiaki Sawatani
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
| | - Annelore Van Mulders
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Nico De Leu
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Department of Endocrinology, University Hospital Brussels, 1090 Brussels, Belgium
- Department of Endocrinology, ASZ Aalst, 9300 Aalst, Belgium
| | - Yves Heremans
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Harry Heimberg
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, 1070 Brussels, Belgium; (T.S.); (M.C.)
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Willem Staels
- Beta Cell Neogenesis (BENE) Research Group, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; (S.B.); (A.V.M.); (N.D.L.); (Y.H.); (H.H.)
- Service of Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, Universitair Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium
- Correspondence: ; Tel.: +32-0-24774473
| |
Collapse
|
|
39
|
Yabe SG, Fukuda S, Nishida J, Takeda F, Nashiro K, Okochi H. Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling. PLoS One 2021; 16:e0245204. [PMID: 33428669 PMCID: PMC7799802 DOI: 10.1371/journal.pone.0245204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/23/2020] [Indexed: 01/15/2023] Open
Abstract
Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.
Collapse
Affiliation(s)
- Shigeharu G Yabe
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Satsuki Fukuda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Junko Nishida
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Fujie Takeda
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kiyoko Nashiro
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hitoshi Okochi
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| |
Collapse
|
|
40
|
Guo K, Tian Q, Yang L, Zhou Z. The Role of Glucagon in Glycemic Variability in Type 1 Diabetes: A Narrative Review. Diabetes Metab Syndr Obes 2021; 14:4865-4873. [PMID: 34992395 PMCID: PMC8710064 DOI: 10.2147/dmso.s343514] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Accepted: 12/01/2021] [Indexed: 01/20/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a progressive disease as a result of the severe destruction of islet β-cell function, which leads to high glucose variability in patients. However, α-cell function is also compromised in patients with T1DM, characterized by aberrant fasting and postprandial glucagon secretion. According to recent studies, this aberrant glucagon secretion plays an increasing role in hyperglycemia, insulin-induced hypoglycemia and exercise-associated hypoglycemia in patients with T1DM. With application of continuous glucose monitoring system, dozens of metrics enable the assessment of glycemic variability, which is an integral component of glycemic control for patients with T1DM. There is growing evidences to illustrate the contribution of glucagon secretion to the glycemic variability in patients with T1DM, which may promote the development of new treatment strategies aiming to mitigate glycemic variability associated with aberrant glucagon secretion.
Collapse
Affiliation(s)
- Keyu Guo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China
| | - Qi Tian
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China
| | - Lin Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China
- Correspondence: Lin Yang; Zhiguang Zhou Email ;
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, People’s Republic of China
| |
Collapse
|
|
41
|
Wu L, Tsang VHM, Sasson SC, Menzies AM, Carlino MS, Brown DA, Clifton-Bligh R, Gunton JE. Unravelling Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside. Front Endocrinol (Lausanne) 2021; 12:764138. [PMID: 34803927 PMCID: PMC8603930 DOI: 10.3389/fendo.2021.764138] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 09/30/2021] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors have transformed the landscape of oncological therapy, but at the price of a new array of immune related adverse events. Among these is β-cell failure, leading to checkpoint inhibitor-related autoimmune diabetes (CIADM) which entails substantial long-term morbidity. As our understanding of this novel disease grows, parallels and differences between CIADM and classic type 1 diabetes (T1D) may provide insights into the development of diabetes and identify novel potential therapeutic strategies. In this review, we outline the knowledge across the disciplines of endocrinology, oncology and immunology regarding the pathogenesis of CIADM and identify possible management strategies.
Collapse
Affiliation(s)
- Linda Wu
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- *Correspondence: Linda Wu,
| | - Venessa H. M. Tsang
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Sarah C. Sasson
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Alexander M. Menzies
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
| | - Matteo S. Carlino
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia
- Department of Medical Oncology, Westmead Hospital, Sydney, NSW, Australia
| | - David A. Brown
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
- Department of Immunology, Westmead Hospital, Sydney, NSW, Australia
- NSW Health Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Sydney, NSW, Australia
| | - Roderick Clifton-Bligh
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | - Jenny E. Gunton
- Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, Sydney, NSW, Australia
- Department of Endocrinology, Westmead Hospital, Sydney, NSW, Australia
- Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| |
Collapse
|
|
42
|
McCarthy O, Pitt J, Churm R, Dunseath GJ, Jones C, Bally L, Nakas CT, Deere R, Eckstein ML, Bain SC, Moser O, Bracken RM. Metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes. BMJ Open Diabetes Res Care 2020; 8:8/1/e001577. [PMID: 33020134 PMCID: PMC7536836 DOI: 10.1136/bmjdrc-2020-001577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/22/2020] [Accepted: 08/19/2020] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION This study sought to compare the metabolomic, hormonal and physiological responses to hypoglycemia versus euglycemia during exercise in adults with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS Thirteen individuals with T1D (hemoglobin; 7.0%±1.3% (52.6±13.9 mmol/mol), age; 36±15 years, duration diabetes; 15±12 years) performed a maximum of 45 min submaximal exercise (60%±6% V̇O2max). Retrospectively identified exercise sessions that ended in hypoglycemia ((HypoEx) blood glucose (BG)≤3.9 mmol/L) were compared against a participant-matched euglycemic condition ((EuEx) BG≥4.0, BG≤10.0 mmol/L). Samples were compared for detailed physiological and hormonal parameters as well as metabolically profiled via large scale targeted ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. Data were assessed using univariate and multivariate analysis techniques with false discovery rate adjustment. Significant results were considered at p≤0.05. RESULTS Cardiorespiratory and counterregulatory hormone responses, whole-body fuel use and perception of fatigue during exercise were similar under conditions of hypoglycemia and euglycemia (BG 3.5±0.3 vs 5.8±1.1 mmol/L, respectively p<0.001). HypoEx was associated with greater adenosine salvage pathway activity (5'-methylthioadenosine, p=0.023 and higher cysteine and methionine metabolism), increased utilization of glucogenic amino acids (glutamine, p=0.021, alanine, aspartate and glutamate metabolism and homoserine/threonine, p=0.045) and evidence of enhanced β-oxidation (lower carnitine p<0.001, higher long-chain acylcarnitines). CONCLUSIONS Exposure to acute hypoglycemia during exercise potentiates alterations in subclinical indices of metabolic stress at the level of the metabolome. However, the physiological responses induced by dynamic physical exercise may mask the symptomatic recognition of mild hypoglycemia during exercise in people with T1D, a potential clinical safety concern that reinforces the need for diligent glucose management. TRIAL REGISTRATION NUMBER DRKS00013509.
Collapse
Affiliation(s)
- Olivia McCarthy
- Applied Sport, Technology, Exercise and Medicine Research Centre (A-STEM), Swansea University College of Engineering, Swansea, UK
| | - Jason Pitt
- Applied Sport, Technology, Exercise and Medicine Research Centre (A-STEM), Swansea University College of Engineering, Swansea, UK
| | - Rachel Churm
- Applied Sport, Technology, Exercise and Medicine Research Centre (A-STEM), Swansea University College of Engineering, Swansea, UK
| | - Gareth J Dunseath
- Diabetes Research Group, Swansea University Medical School, Swansea, UK
| | - Charlotte Jones
- Diabetes Research Group, Swansea University Medical School, Swansea, UK
| | - Lia Bally
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital University Hospital Bern, Bern, Switzerland
| | - Christos T Nakas
- Laboratory of Biometry, University of Thessaly, Volos, Thessaly, Greece
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Rachel Deere
- Department of Health, University of Bath, Bath, Somerset, UK
| | - Max L Eckstein
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Stephen C Bain
- Diabetes Research Group, Swansea University Medical School, Swansea, UK
| | - Othmar Moser
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Richard M Bracken
- Applied Sport, Technology, Exercise and Medicine Research Centre (A-STEM), Swansea University College of Engineering, Swansea, UK
| |
Collapse
|
|
43
|
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.
Collapse
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.
| |
Collapse
|
|
44
|
Major S, El Fathi A, Palisaitis E, Kearney R, Von Oettingen JE, Krishnamoorthy P, Legault L, Haidar A. Postprandial hyperglycaemia following insulin suspensions by the artificial pancreas: Implications for bolus calculators. Diabetes Obes Metab 2020; 22:1474-1477. [PMID: 32533655 DOI: 10.1111/dom.14044] [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: 02/06/2020] [Revised: 03/27/2020] [Accepted: 03/29/2020] [Indexed: 11/29/2022]
Abstract
Conventional bolus calculators apply negative prandial corrections when premeal glucose levels are low. However, no study has evaluated the need for this negative correction with closed-loop systems. We analysed data retrospectively from a cohort study evaluating a closed-loop artificial pancreas system conducted in a diabetes camp over a period of 11 days. Meal boluses with negative correction (n = 98) of 47 participants aged 8 to 22 years were examined. If there was no insulin-on-board from previous boluses at mealtime, the postprandial hyperglycaemia rate increased with increased duration of insulin suspension (P = .03), with odds ratios being exaggerated by 17% per 10 minutes of suspension. However, if there was insulin-on-board from previous boluses, the hyperglycaemia rate did not change with increased duration of insulin suspension (P = .24). When there was no insulin-on-board, the rate of hyperglycaemia after meals preceded by no suspension was 21% (3/14), compared with 52% (12/23) and 64% (9/14) after meals preceded by suspensions of ≥50 and ≥70 minutes, respectively. Meal size did not influence these results. We conclude that, in the absence of insulin-on-board, negative prandial corrections may not be necessary following long insulin suspensions.
Collapse
Affiliation(s)
- Sandrine Major
- Department of Biomedical Engineering, McGill University, Montréal, Quebec, Canada
| | - Anas El Fathi
- Department of Electrical and Computer Engineering, McGill University, Montréal, Quebec, Canada
| | - Emilie Palisaitis
- Department of Biomedical Engineering, McGill University, Montréal, Quebec, Canada
| | - Robert Kearney
- Department of Biomedical Engineering, McGill University, Montréal, Quebec, Canada
| | - Julia E Von Oettingen
- Montreal Children's Hospital, McGill University Health Centre, Montréal, Quebec, Canada
- The Research Institute of McGill University Health Centre, Montréal, Quebec, Canada
| | | | - Laurent Legault
- Montreal Children's Hospital, McGill University Health Centre, Montréal, Quebec, Canada
| | - Ahmad Haidar
- Department of Biomedical Engineering, McGill University, Montréal, Quebec, Canada
- The Research Institute of McGill University Health Centre, Montréal, Quebec, Canada
| |
Collapse
|
|
45
|
Pilgaard KA, Breinegaard N, Johannesen J, Pörksen S, Fredheim S, Madsen M, Kristensen K, Svensson J, Birkebaek NH. Episodes of severe hypoglycemia is associated with a progressive increase in hemoglobin A1c in children and adolescents with type 1 diabetes. Pediatr Diabetes 2020; 21:808-813. [PMID: 32304129 DOI: 10.1111/pedi.13020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 03/01/2020] [Accepted: 04/02/2020] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE To investigate the trajectory in glycemic control following episodes of severe hypoglycemia (SH) among children and adolescents with type 1 diabetes (T1D). METHODS A Danish national population-based study comprising data from 2008-17. SH was defined according to the 2014 ISPAD guidelines. A mixed model was applied with HbA1c as outcome and SH episodes and time since first episode as explanatory variables. Data were adjusted for age, gender and diabetes duration. RESULTS A total of 4244 children (51.6% boys) with 18 793 annual outpatient visits were included. Mean (SD) age at diabetes onset was 9.0 (4.1) years. Median diabetes duration at inclusion in the study was 1.2 (Q1 = 0.9, Q3 = 3.0) years, and median diabetes duration at last visit was 5.0 (Q1 = 2.7, Q3 = 8.1) years. A total of 506 children experienced at least one episode of SH during the nine-year follow-up; 294 children experienced one episode, 115 two episodes and 97 three or more episodes of SH. HbA1c increased with episodes of SH and in the years following the first episode. The glycemic trajectory peaked 2 to 3 years after an SH episode. The accumulated deterioration in glycemic control was in the range of 5% in patients with two or more episodes equivalent to an increase in HbA1c of 4 mmol/mol (HbA1c ~0.4%). CONCLUSION SH was followed by a progressive and lasting increase in HbA1c among Danish children and adolescents with T1D. Thus, in addition to the known risk of new episodes of hypoglycemia and cognitive impairment, SH contributes to long-term diabetes complications.
Collapse
Affiliation(s)
- Kasper A Pilgaard
- Department of Paediatrics, Nordsjaellands Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Nina Breinegaard
- Department of Biostatistics, University of Copenhagen, Kobenhavn, Denmark
| | - Jesper Johannesen
- Department of Paediatrics, Herlev University Hospital, Herlev, Denmark
| | - Sven Pörksen
- Department of Paediatrics, Roskilde University Hospital, Roskilde, Denmark.,Steno Diabetes Center Region of Zealand, Roskilde, Denmark
| | - Siri Fredheim
- Steno Diabetes Center Region of Zealand, Roskilde, Denmark.,Department of Paediatrics, Sjaellands University Hospital, Roskilde, Denmark
| | - Mette Madsen
- Department of Paediatrics, Aalborg University Hospital, Aalborg, Denmark
| | - Kurt Kristensen
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Jannet Svensson
- Department of Paediatrics, Herlev University Hospital, Herlev, Denmark
| | - Niels H Birkebaek
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.,Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| |
Collapse
|
|
46
|
Viloria K, Nasteska D, Briant LJB, Heising S, Larner DP, Fine NHF, Ashford FB, da Silva Xavier G, Ramos MJ, Hasib A, Cuozzo F, Manning Fox JE, MacDonald PE, Akerman I, Lavery GG, Flaxman C, Morgan NG, Richardson SJ, Hewison M, Hodson DJ. Vitamin-D-Binding Protein Contributes to the Maintenance of α Cell Function and Glucagon Secretion. Cell Rep 2020; 31:107761. [PMID: 32553153 PMCID: PMC7302426 DOI: 10.1016/j.celrep.2020.107761] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 04/22/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
Vitamin-D-binding protein (DBP) or group-specific component of serum (GC-globulin) carries vitamin D metabolites from the circulation to target tissues. DBP is highly localized to the liver and pancreatic α cells. Although DBP serum levels, gene polymorphisms, and autoantigens have all been associated with diabetes risk, the underlying mechanisms remain unknown. Here, we show that DBP regulates α cell morphology, α cell function, and glucagon secretion. Deletion of DBP leads to smaller and hyperplastic α cells, altered Na+ channel conductance, impaired α cell activation by low glucose, and reduced rates of glucagon secretion both in vivo and in vitro. Mechanistically, this involves reversible changes in islet microfilament abundance and density, as well as changes in glucagon granule distribution. Defects are also seen in β cell and δ cell function. Immunostaining of human pancreata reveals generalized loss of DBP expression as a feature of late-onset and long-standing, but not early-onset, type 1 diabetes. Thus, DBP regulates α cell phenotype, with implications for diabetes pathogenesis.
Collapse
Affiliation(s)
- Katrina Viloria
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Daniela Nasteska
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Linford J B Briant
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7LE, UK
| | - Silke Heising
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Dean P Larner
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Nicholas H F Fine
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Fiona B Ashford
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Gabriela da Silva Xavier
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Maria Jiménez Ramos
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Annie Hasib
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Federica Cuozzo
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK
| | - Jocelyn E Manning Fox
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Patrick E MacDonald
- Department of Pharmacology and Alberta Diabetes Institute, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Ildem Akerman
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Gareth G Lavery
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK
| | - Christine Flaxman
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
| | - Noel G Morgan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
| | - Sarah J Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK
| | - Martin Hewison
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK.
| | - David J Hodson
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham B15 2TT, UK; Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TT, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands, UK.
| |
Collapse
|
|
47
|
A method for the generation of human stem cell-derived alpha cells. Nat Commun 2020; 11:2241. [PMID: 32382023 PMCID: PMC7205884 DOI: 10.1038/s41467-020-16049-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 04/10/2020] [Indexed: 01/14/2023] Open
Abstract
The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate. These pre-alpha cells exhibit a transcriptional profile similar to mature alpha cells and although they produce proinsulin protein, they do not secrete significant amounts of processed insulin. Compound screening identified a protein kinase c activator that promotes maturation of pre-alpha cells into SC-alpha cells. The resulting SC-alpha cells do not express insulin, share an ultrastructure similar to cadaveric alpha cells, express and secrete glucagon in response to glucose and some glucagon secretagogues, and elevate blood glucose upon transplantation in mice.
Collapse
|
|
48
|
Rickels MR, Evans-Molina C, Bahnson HT, Ylescupidez A, Nadeau KJ, Hao W, Clements MA, Sherr JL, Pratley RE, Hannon TS, Shah VN, Miller KM, Greenbaum CJ. High residual C-peptide likely contributes to glycemic control in type 1 diabetes. J Clin Invest 2020; 130:1850-1862. [PMID: 31895699 PMCID: PMC7108933 DOI: 10.1172/jci134057] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 12/26/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUNDResidual C-peptide is detected in many people for years following the diagnosis of type 1 diabetes; however, the physiologic significance of low levels of detectable C-peptide is not known.METHODSWe studied 63 adults with type 1 diabetes classified by peak mixed-meal tolerance test (MMTT) C-peptide as negative (<0.007 pmol/mL; n = 15), low (0.017-0.200; n = 16), intermediate (>0.200-0.400; n = 15), or high (>0.400; n = 17). We compared the groups' glycemia from continuous glucose monitoring (CGM), β cell secretory responses from a glucose-potentiated arginine (GPA) test, insulin sensitivity from a hyperinsulinemic-euglycemic (EU) clamp, and glucose counterregulatory responses from a subsequent hypoglycemic (HYPO) clamp.RESULTSLow and intermediate MMTT C-peptide groups did not exhibit β cell secretory responses to hyperglycemia, whereas the high C-peptide group showed increases in both C-peptide and proinsulin (P ≤ 0.01). All groups with detectable MMTT C-peptide demonstrated acute C-peptide and proinsulin responses to arginine that were positively correlated with peak MMTT C-peptide (P < 0.0001 for both analytes). During the EU-HYPO clamp, C-peptide levels were proportionately suppressed in the low, intermediate, and high C-peptide compared with the negative group (P ≤ 0.0001), whereas glucagon increased from EU to HYPO only in the high C-peptide group compared with negative (P = 0.01). CGM demonstrated lower mean glucose and more time in range for the high C-peptide group.CONCLUSIONThese results indicate that in adults with type 1 diabetes, β cell responsiveness to hyperglycemia and α cell responsiveness to hypoglycemia are observed only at high levels of residual C-peptide that likely contribute to glycemic control.FUNDINGFunding for this work was provided by the Leona M. and Harry B. Helmsley Charitable Trust, the National Center for Advancing Translational Sciences, and the National Institute of Diabetes and Digestive and Kidney Diseases.
Collapse
Affiliation(s)
- Michael R. Rickels
- Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Carmella Evans-Molina
- Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | | | | | - Kristen J. Nadeau
- Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Wei Hao
- Benaroya Research Institute, Seattle, Washington, USA
| | | | | | - Richard E. Pratley
- AdventHealth Translational Research Institute for Metabolism and Diabetes, Orlando, Florida, USA
| | - Tamara S. Hannon
- Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Viral N. Shah
- Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, Colorado, USA
| | | | | | | |
Collapse
|
|
49
|
Bru-Tari E, Oropeza D, Herrera PL. Cell Heterogeneity and Paracrine Interactions in Human Islet Function: A Perspective Focused in β-Cell Regeneration Strategies. Front Endocrinol (Lausanne) 2020; 11:619150. [PMID: 33613453 PMCID: PMC7888438 DOI: 10.3389/fendo.2020.619150] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/14/2020] [Indexed: 12/27/2022] Open
Abstract
The β-cell regeneration field has shown a strong knowledge boost in the last 10 years. Pluripotent stem cell differentiation and direct reprogramming from other adult cell types are becoming more tangible long-term diabetes therapies. Newly generated β-like-cells consistently show hallmarks of native β-cells and can restore normoglycemia in diabetic mice in virtually all recent studies. Nonetheless, these cells still show important compromises in insulin secretion, cell metabolism, electrical activity, and overall survival, perhaps due to a lack of signal integration from other islet cells. Mounting data suggest that diabetes is not only a β-cell disease, as the other islet cell types also contribute to its physiopathology. Here, we present an update on the most recent studies of islet cell heterogeneity and paracrine interactions in the context of restoring an integrated islet function to improve β-cell replacement therapies.
Collapse
|
|
50
|
Dimitrios P, Michael D, Vasilios K, Konstantinos S, Konstantinos I, Ioanna Z, Konstantinos P, Spyridon B, Asterios K. Liraglutide as Adjunct to Insulin Treatment in Patients with Type 1 Diabetes: A Systematic Review and Meta-analysis. Curr Diabetes Rev 2020; 16:313-326. [PMID: 31203802 DOI: 10.2174/1573399815666190614141918] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 03/24/2019] [Accepted: 05/03/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND A few Randomized Controlled Trials (RCTs) have evaluated the use of liraglutide in Type 1 Diabetes (T1D). Through the present systematic review and meta-analysis, we aim at critically appraising and summarizing those RCTs, providing precise effect estimates. METHODS We searched major databases and grey literature from their inception to October 2018, for RCTs with a duration ≥ 12 weeks, comparing liraglutide with placebo or any other comparator as adjunct to insulin in patients with T1D, investigating major efficacy and safety endpoints. This review is reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. RESULTS We included 5 trials with 2,445 randomized participants. Liraglutide provided modest reductions in HbA1c, with liraglutide 1.8 mg producing the greatest decrease (MD = -0.24%, 95% CI -0.32 to -0.16, I2=0%). Significant weight reduction, up to 4.87 kg with liraglutide 1.8 mg was also observed (95% CI -5.31 to -4.43, I2=0%). Decrease in total daily insulin dose, primarily driven by a decrease in bolus insulin requirements, was demonstrated. Liraglutide decreased non-significantly the odds for severe hypoglycemia (OR=0.80, 95% CI 0.57-1.14, I2=0%), while it increased significantly the odds for gastrointestinal adverse events (for nausea, OR=4.70, 95% CI 3.68-6.00, I2=37%, and for vomiting, OR=2.50, 95% CI 1.54-4.72, I2=27%). A significant increase in heart rate was also demonstrated. No association with diabetic ketoacidosis or malignancies was identified. CONCLUSION In patients with T1D, liraglutide might prove be an adjunct to insulin, improving glycemic control, inducing body weight loss and decreasing exogenous insulin requirements and severe hypoglycemia.
Collapse
Affiliation(s)
- Patoulias Dimitrios
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Doumas Michael
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
- VAMC and George Washington University, Washington, DC, United States
| | - Kotsis Vasilios
- Third Department of Internal Medicine, General Hospital "Papageorgiou", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stavropoulos Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Imprialos Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Zografou Ioanna
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Petidis Konstantinos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Bakatselos Spyridon
- First Department of Internal Medicine, General Hospital "Hippokration", Thessaloniki, Greece
| | - Karagiannis Asterios
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| |
Collapse
|