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Tura A, Göbl C, El-Tanani M, Rizzo M. In-silico modelling of insulin secretion and pancreatic beta-cell function for clinical applications: is it worth the effort? FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2024; 5:1452400. [PMID: 39559404 PMCID: PMC11570995 DOI: 10.3389/fcdhc.2024.1452400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 08/29/2024] [Indexed: 11/20/2024]
Affiliation(s)
- Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Mohamed El-Tanani
- College of Pharmacy, Ras Al Khaimah Medical and Health Sciences University, Ras Al Khaimah, United Arab Emirates
| | - Manfredi Rizzo
- School of Medicine, Mohammed Bin Rashid University, Dubai, United Arab Emirates
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, School of Medicine, University of Palermo, Palermo, Italy
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Sabadell-Basallote J, Astiarraga B, Castaño C, Ejarque M, Repollés-de-Dalmau M, Quesada I, Blanco J, Núñez-Roa C, Rodríguez-Peña MM, Martínez L, De Jesus DF, Marroquí L, Bosch R, Montanya E, Sureda FX, Tura A, Mari A, Kulkarni RN, Vendrell J, Fernández-Veledo S. SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes. J Clin Invest 2024; 134:e173214. [PMID: 38713514 PMCID: PMC11178533 DOI: 10.1172/jci173214] [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: 06/21/2023] [Accepted: 04/26/2024] [Indexed: 05/09/2024] Open
Abstract
Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β cells. Mice with β cell-specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
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Affiliation(s)
- Joan Sabadell-Basallote
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Brenno Astiarraga
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Castaño
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Miriam Ejarque
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Maria Repollés-de-Dalmau
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Ivan Quesada
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Alicante, Spain
| | | | - Catalina Núñez-Roa
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - M-Mar Rodríguez-Peña
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Laia Martínez
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
| | - Dario F. De Jesus
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Laura Marroquí
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Alicante, Spain
| | - Ramon Bosch
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
- Histological, Cytological and Digitization Studies Platform, Pathology Department, Hospital Verge de la Cinta, Tortosa, Spain
| | - Eduard Montanya
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Hospital Universitari de Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), and Universitat de Barcelona, Barcelona, Spain
| | | | - Andrea Tura
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Rohit N. Kulkarni
- Islet Cell and Regenerative Biology, Joslin Diabetes Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Joan Vendrell
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
| | - Sonia Fernández-Veledo
- Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d’Investigació Sanitària Pere Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
- Universitat Rovira i Virgili, Tarragona, Spain
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Subramanian V, Bagger JI, Harihar V, Holst JJ, Knop FK, Villsbøll T. An extended minimal model of OGTT: estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect. Am J Physiol Endocrinol Metab 2024; 326:E182-E205. [PMID: 38088864 PMCID: PMC11193523 DOI: 10.1152/ajpendo.00278.2023] [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: 08/28/2023] [Revised: 11/27/2023] [Accepted: 12/07/2023] [Indexed: 12/20/2023]
Abstract
Loss of insulin sensitivity, α- and β-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, β- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and β-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.
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Affiliation(s)
- Vijaya Subramanian
- Institute for Computational Medicine, Johns Hopkins University, Baltimore, Maryland, United States
| | - Jonatan I Bagger
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Vinayak Harihar
- Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, United States
- Biophysics Graduate Group, University of California, Berkeley, California, United States
| | - Jens J 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
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Tina Villsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Salvatori B, Linder T, Eppel D, Morettini M, Burattini L, Göbl C, Tura A. TyGIS: improved triglyceride-glucose index for the assessment of insulin sensitivity during pregnancy. Cardiovasc Diabetol 2022; 21:215. [PMID: 36258194 PMCID: PMC9580191 DOI: 10.1186/s12933-022-01649-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 09/28/2022] [Indexed: 11/21/2022] Open
Abstract
Background The triglyceride-glucose index (TyG) has been proposed as a surrogate marker of insulin resistance, which is a typical trait of pregnancy. However, very few studies analyzed TyG performance as marker of insulin resistance in pregnancy, and they were limited to insulin resistance assessment at fasting rather than in dynamic conditions, i.e., during an oral glucose tolerance test (OGTT), which allows more reliable assessment of the actual insulin sensitivity impairment. Thus, first aim of the study was exploring in pregnancy the relationships between TyG and OGTT-derived insulin sensitivity. In addition, we developed a new version of TyG, for improved performance as marker of insulin resistance in pregnancy. Methods At early pregnancy, a cohort of 109 women underwent assessment of maternal biometry and blood tests at fasting, for measurements of several variables (visit 1). Subsequently (26 weeks of gestation) all visit 1 analyses were repeated (visit 2), and a subgroup of women (84 selected) received a 2 h-75 g OGTT (30, 60, 90, and 120 min sampling) with measurement of blood glucose, insulin and C-peptide for reliable assessment of insulin sensitivity (PREDIM index) and insulin secretion/beta-cell function. The dataset was randomly split into 70% training set and 30% test set, and by machine learning approach we identified the optimal model, with TyG included, showing the best relationship with PREDIM. For inclusion in the model, we considered only fasting variables, in agreement with TyG definition. Results The relationship of TyG with PREDIM was weak. Conversely, the improved TyG, called TyGIS, (linear function of TyG, body weight, lean body mass percentage and fasting insulin) resulted much strongly related to PREDIM, in both training and test sets (R2 > 0.64, p < 0.0001). Bland–Altman analysis and equivalence test confirmed the good performance of TyGIS in terms of association with PREDIM. Different further analyses confirmed TyGIS superiority over TyG. Conclusions We developed an improved version of TyG, as new surrogate marker of insulin sensitivity in pregnancy (TyGIS). Similarly to TyG, TyGIS relies only on fasting variables, but its performances are remarkably improved than those of TyG. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01649-8.
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Affiliation(s)
| | - Tina Linder
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090, Vienna, Austria
| | - Daniel Eppel
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090, Vienna, Austria
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica Delle Marche, 60131, Ancona, Italy
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica Delle Marche, 60131, Ancona, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090, Vienna, Austria
| | - Andrea Tura
- CNR Institute of Neuroscience, Corso Stati Uniti 4, 35127, Padua, Italy.
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Göbl C, Tura A. Letter to the Editor From Göbl and Tura: "Oral Glucose Tolerance Test-based Measures of Insulin Secretory Response in Pregnancy". J Clin Endocrinol Metab 2022; 107:e4270-e4271. [PMID: 35907181 DOI: 10.1210/clinem/dgac423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Indexed: 11/19/2022]
Affiliation(s)
- Christian Göbl
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090 Vienna, Austria
| | - Andrea Tura
- CNR Institute of Neuroscience, 35127 Padova, Italy
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Morettini M, Palumbo MC, Göbl C, Burattini L, Karusheva Y, Roden M, Pacini G, Tura A. Mathematical model of insulin kinetics accounting for the amino acids effect during a mixed meal tolerance test. Front Endocrinol (Lausanne) 2022; 13:966305. [PMID: 36187117 PMCID: PMC9519856 DOI: 10.3389/fendo.2022.966305] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/25/2022] [Indexed: 11/30/2022] Open
Abstract
Amino acids (AAs) are well known to be involved in the regulation of glucose metabolism and, in particular, of insulin secretion. However, the effects of different AAs on insulin release and kinetics have not been completely elucidated. The aim of this study was to propose a mathematical model that includes the effect of AAs on insulin kinetics during a mixed meal tolerance test. To this aim, five different models were proposed and compared. Validation was performed using average data, derived from the scientific literature, regarding subjects with normal glucose tolerance (CNT) and with type 2 diabetes (T2D). From the average data of the CNT and T2D people, data for two virtual populations (100 for each group) were generated for further model validation. Among the five proposed models, a simple model including one first-order differential equation showed the best results in terms of model performance (best compromise between model structure parsimony, estimated parameters plausibility, and data fit accuracy). With regard to the contribution of AAs to insulin appearance/disappearance (kAA model parameter), model analysis of the average data from the literature yielded 0.0247 (confidence interval, CI: 0.0168 - 0.0325) and -0.0048 (CI: -0.0281 - 0.0185) μU·ml-1/(μmol·l-1·min), for CNT and T2D, respectively. This suggests a positive effect of AAs on insulin secretion in CNT, and negligible effect in T2D. In conclusion, a simple model, including single first-order differential equation, may help to describe the possible AAs effects on insulin kinetics during a physiological metabolic test, and provide parameters that can be assessed in the single individuals.
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Affiliation(s)
- Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | | | - Christian Göbl
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Yanislava Karusheva
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Neuherberg, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University, Düsseldorf, Germany
| | | | - Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
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Assessing the Effect of Incretin Hormones and Other Insulin Secretagogues on Pancreatic Beta-Cell Function: Review on Mathematical Modelling Approaches. Biomedicines 2022; 10:biomedicines10051060. [PMID: 35625797 PMCID: PMC9138583 DOI: 10.3390/biomedicines10051060] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 04/25/2022] [Accepted: 04/28/2022] [Indexed: 11/16/2022] Open
Abstract
Mathematical modelling in glucose metabolism has proven very useful for different reasons. Several models have allowed deeper understanding of the relevant physiological and pathophysiological aspects and promoted new experimental activity to reach increased knowledge of the biological and physiological systems of interest. Glucose metabolism modelling has also proven useful to identify the parameters with specific physiological meaning in single individuals, this being relevant for clinical applications in terms of precision diagnostics or therapy. Among those model-based physiological parameters, an important role resides in those for the assessment of different functional aspects of the pancreatic beta cell. This study focuses on the mathematical models of incretin hormones and other endogenous substances with known effects on insulin secretion and beta-cell function, mainly amino acids, non-esterified fatty acids, and glucagon. We found that there is a relatively large number of mathematical models for the effects on the beta cells of incretin hormones, both at the cellular/organ level or at the higher, whole-body level. In contrast, very few models were identified for the assessment of the effect of other insulin secretagogues. Given the opportunities offered by mathematical modelling, we believe that novel models in the investigated field are certainly advisable.
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Tura A, Göbl C, Vardarli I, Pacini G, Nauck M. Insulin clearance and incretin hormones following oral and "isoglycemic" intravenous glucose in type 2 diabetes patients under different antidiabetic treatments. Sci Rep 2022; 12:2510. [PMID: 35169165 PMCID: PMC8847358 DOI: 10.1038/s41598-022-06402-5] [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: 10/06/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7-36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.
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Affiliation(s)
- Andrea Tura
- CNR Institute of Neuroscience, Corso Stati Uniti 4, 35127, Padova, Italy.
| | - Christian Göbl
- Department of Obstetrics and Gynaecology, Medical University of Vienna, Vienna, Austria
| | - Irfan Vardarli
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital (Ruhr University Bochum), Bochum, Germany
| | | | - Michael Nauck
- Diabetes Division, Katholisches Klinikum Bochum, St. Josef Hospital (Ruhr University Bochum), Bochum, Germany
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Göbl C, Morettini M, Salvatori B, Alsalim W, Kahleova H, Ahrén B, Tura A. Temporal Patterns of Glucagon and Its Relationships with Glucose and Insulin following Ingestion of Different Classes of Macronutrients. Nutrients 2022; 14:nu14020376. [PMID: 35057557 PMCID: PMC8780023 DOI: 10.3390/nu14020376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 01/27/2023] Open
Abstract
Background: glucagon secretion and inhibition should be mainly determined by glucose and insulin levels, but the relative relevance of each factor is not clarified, especially following ingestion of different macronutrients. We aimed to investigate the associations between plasma glucagon, glucose, and insulin after ingestion of single macronutrients or mixed-meal. Methods: thirty-six participants underwent four metabolic tests, based on administration of glucose, protein, fat, or mixed-meal. Glucagon, glucose, insulin, and C-peptide were measured at fasting and for 300 min following food ingestion. We analyzed relationships between time samples of glucagon, glucose, and insulin in each individual, as well as between suprabasal area-under-the-curve of the same variables (ΔAUCGLUCA, ΔAUCGLU, ΔAUCINS) over the whole participants’ cohort. Results: in individuals, time samples of glucagon and glucose were related in only 26 cases (18 direct, 8 inverse relationships), whereas relationship with insulin was more frequent (60 and 5, p < 0.0001). The frequency of significant relationships was different among tests, especially for direct relationships (p ≤ 0.006). In the whole cohort, ΔAUCGLUCA was weakly related to ΔAUCGLU (p ≤ 0.02), but not to ΔAUCINS, though basal insulin secretion emerged as possible covariate. Conclusions: glucose and insulin are not general and exclusive determinants of glucagon secretion/inhibition after mixed-meal or macronutrients ingestion.
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Affiliation(s)
- Christian Göbl
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, 60131 Ancona, Italy;
| | | | - Wathik Alsalim
- Department of Clinical Sciences, Faculty of Medicine, Lund University, 22184 Lund, Sweden; (W.A.); (B.A.)
| | - Hana Kahleova
- Physicians Committee for Responsible Medicine, Washington, DC 20016, USA;
| | - Bo Ahrén
- Department of Clinical Sciences, Faculty of Medicine, Lund University, 22184 Lund, Sweden; (W.A.); (B.A.)
| | - Andrea Tura
- CNR Institute of Neuroscience, 35127 Padova, Italy;
- Correspondence: ; Tel.: +39-049-829-5786
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Chueire VB, Muscelli E. Effect of free fatty acids on insulin secretion, insulin sensitivity and incretin effect - a narrative review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2021; 65:24-31. [PMID: 33320449 PMCID: PMC10528699 DOI: 10.20945/2359-3997000000313] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 09/26/2020] [Indexed: 11/23/2022]
Abstract
Deleterious effects of free fatty acids, FFAs, on insulin sensitivity are observed in vivo studies in humans. Mechanisms include impaired insulin signaling, oxidative stress, inflammation, and mitochondrial dysfunction, but the effects on insulin secretion are less well known. Our aim was to review the relationship of increased FFAs with insulin resistance, secretion and mainly with the incretin effect in humans. Narrative review. Increased endogenous or administered FFAs induce insulin resistance. FFAs effects on insulin secretion are debatable; inhibition and stimulation have been reported, depending on the type and duration of lipids exposition and the study subjects. Chronically elevated FFAs seem to decrease insulin biosynthesis, glucose-stimulated insulin secretion and β-cell glucose sensitivity. Lipids infusion decreases the response to incretins with unchanged incretin levels in volunteers with normal glucose tolerance. In contrast, FFAs reduction by acipimox did not restore the incretin effect in type-2 diabetes, probably due to the dysfunctional β-cell. Possible mechanisms of FFAs excess on incretin effect include reduction of the expression and levels of GLP-1 (glucagon like peptide-1) receptor, reduction of connexin-36 expression thus the coordinated secretory activity in response to GLP-1, and GIP (glucose-dependent insulinotropic polypeptide) receptors downregulation in islets cells. Increased circulating FFAs impair insulin sensitivity. Effects on insulin secretion are complex and controversial. Deleterious effects on the incretin-induced potentiation of insulin secretion were reported. More investigation is needed to better understand the extent and mechanisms of β-cell impairment and insulin resistance induced by increased FFAs and how to prevent them.
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Affiliation(s)
- Valeria Bahdur Chueire
- Departamento de Endocrinologia, Hospital da Pontifícia Universidade Católica de Campinas, Campinas, SP, Brasil,
| | - Elza Muscelli
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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Tura A, Grespan E, Göbl CS, Koivula RW, Franks PW, Pearson ER, Walker M, Forgie IM, Giordano GN, Pavo I, Ruetten H, Dermitzakis ET, McCarthy MI, Pedersen O, Schwenk JM, Adamski J, De Masi F, Tsirigos KD, Brunak S, Viñuela A, Mahajan A, McDonald TJ, Kokkola T, Vangipurapu J, Cederberg H, Laakso M, Rutters F, Elders PJM, Koopman ADM, Beulens JW, Ridderstråle M, Hansen TH, Allin KH, Hansen T, Vestergaard H, Mari A. Profiles of Glucose Metabolism in Different Prediabetes Phenotypes, Classified by Fasting Glycemia, 2-Hour OGTT, Glycated Hemoglobin, and 1-Hour OGTT: An IMI DIRECT Study. Diabetes 2021; 70:2092-2106. [PMID: 34233929 DOI: 10.2337/db21-0227] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 06/24/2021] [Indexed: 11/13/2022]
Abstract
Differences in glucose metabolism among categories of prediabetes have not been systematically investigated. In this longitudinal study, participants (N = 2,111) underwent a 2-h 75-g oral glucose tolerance test (OGTT) at baseline and 48 months. HbA1c was also measured. We classified participants as having isolated prediabetes defect (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], or HbA1c indicative of prediabetes [IA1c]), two defects (IFG+IGT, IFG+IA1c, or IGT+IA1c), or all defects (IFG+IGT+IA1c). β-Cell function (BCF) and insulin sensitivity were assessed from OGTT. At baseline, in pooling of participants with isolated defects, they showed impairment in both BCF and insulin sensitivity compared with healthy control subjects. Pooled groups with two or three defects showed progressive further deterioration. Among groups with isolated defect, those with IGT showed lower insulin sensitivity, insulin secretion at reference glucose (ISRr), and insulin secretion potentiation (P < 0.002). Conversely, those with IA1c showed higher insulin sensitivity and ISRr (P < 0.0001). Among groups with two defects, we similarly found differences in both BCF and insulin sensitivity. At 48 months, we found higher type 2 diabetes incidence for progressively increasing number of prediabetes defects (odds ratio >2, P < 0.008). In conclusion, the prediabetes groups showed differences in type/degree of glucometabolic impairment. Compared with the pooled group with isolated defects, those with double or triple defect showed progressive differences in diabetes incidence.
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Affiliation(s)
- Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
| | | | - Christian S Göbl
- Division of Obstetrics and Feto-Maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Robert W Koivula
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K
- Genetic and Molecular Epidemiology, Department of Clinical Science, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Paul W Franks
- Genetic and Molecular Epidemiology, Department of Clinical Science, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Ewan R Pearson
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, U.K
| | - Mark Walker
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
| | - Ian M Forgie
- Population Health and Genomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, U.K
| | - Giuseppe N Giordano
- Genetic and Molecular Epidemiology, Department of Clinical Science, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Imre Pavo
- Eli Lilly Regional Operations Ges.m.b.H., Vienna, Austria
| | - Hartmut Ruetten
- CardioMetabolism & Respiratory Medicine, Boehringer Ingelheim International GmbH, Ingelheim/Rhein, Germany
| | - Emmanouil T Dermitzakis
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
| | - Mark I McCarthy
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K
| | - Oluf Pedersen
- Section of Metabolic Genetics, Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Jochen M Schwenk
- Affinity Proteomics, Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Solna, Sweden
| | - Jerzy Adamski
- Institute of Experimental Genetics, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Federico De Masi
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Disease Systems Biology Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Konstantinos D Tsirigos
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Disease Systems Biology Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Søren Brunak
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
- Disease Systems Biology Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ana Viñuela
- Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, U.K
| | - Anubha Mahajan
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K
| | - Timothy J McDonald
- Blood Sciences, Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K
| | - Tarja Kokkola
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Jagadish Vangipurapu
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Henna Cederberg
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Markku Laakso
- Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Femke Rutters
- Department of Epidemiology and Data Science, Amsterdam Medical Centre, location VUMC, Amsterdam, the Netherlands
| | - Petra J M Elders
- Department of Epidemiology and Data Science, Amsterdam Medical Centre, location VUMC, Amsterdam, the Netherlands
| | - Anitra D M Koopman
- Department of Epidemiology and Data Science, Amsterdam Medical Centre, location VUMC, Amsterdam, the Netherlands
| | - Joline W Beulens
- Department of Epidemiology and Data Science, Amsterdam Medical Centre, location VUMC, Amsterdam, the Netherlands
| | - Martin Ridderstråle
- Department of Clinical Sciences, Diabetes & Endocrinology Unit, Lund University, Skåne University Hospital Malmö, Malmö, Sweden
| | - Tue H Hansen
- Section of Metabolic Genetics, Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Kristine H Allin
- Section of Metabolic Genetics, Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Torben Hansen
- Section of Metabolic Genetics, Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Vestergaard
- Section of Metabolic Genetics, Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Department of Medicine, Bornholms Hospital, Rønne, Denmark
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Mambelli E, Cristino S, Mosconi G, Göbl C, Tura A. Flash Glucose Monitoring to Assess Glycemic Control and Variability in Hemodialysis Patients: The GIOTTO Study. Front Med (Lausanne) 2021; 8:617891. [PMID: 34395456 PMCID: PMC8360859 DOI: 10.3389/fmed.2021.617891] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 06/28/2021] [Indexed: 12/17/2022] Open
Abstract
Background: Flash glucose monitoring (FGM) is a technology with considerable differences compared to continuous glucose monitoring (CGM), but it has been scarcely studied in hemodialysis patients. Thus, we aimed assessing the performance of FGM in such patients by comparison to self-monitoring of blood glucose (SMBG). We will also focus on estimation of glycemic control and variability, and their relationships with parameters of glucose homeostasis. Methods: Thirty-one patients (20 with type 2 diabetes, T2DM, 11 diabetes-free, NODM) collected readings by FGM and SMBG for about 12 days on average. Readings by FGM and SMBG were compared by linear regression, Clarke error grid, and Bland-Altman analyses. Several indices of glycemic control and variability were computed. Ten patients also underwent oral glucose tolerance test (OGTT) for assessment of insulin sensitivity/resistance and insulin secretion/beta-cell function. Results: Flash glucose monitoring and SMBG readings showed very good agreement in both T2DM and NODM (on average, 97 and 99% of readings during hemodialysis in A+B Clarke regions, respectively). Some glycemic control and variability indices were similar by FGM and SMBG (p = 0.06–0.9), whereas others were different (p = 0.0001–0.03). The majority of control and variability indices were higher in T2DM than in NODM, according to both FGM and SMBG (p = 0.0005–0.03). OGTT-based insulin secretion was inversely related to some variability indices according to FGM (R < −0.72, p < 0.02). Conclusions: Based on our dataset, FGM appeared acceptable for glucose monitoring in hemodialysis patients, though partial disagreement with SMBG in glycemic control/variability assessment needs further investigations.
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Affiliation(s)
- Emanuele Mambelli
- Nephrology and Dialysis, Bufalini Hospital, AUSL Romagna, Cesena, Italy
| | - Stefania Cristino
- Nephrology and Dialysis, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Giovanni Mosconi
- Nephrology and Dialysis, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Vienna, Austria
| | - Andrea Tura
- CNR Institute of Neuroscience, Padova, Italy
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Cordiner RLM, Mari A, Tura A, Pearson ER. The Impact of Low-dose Gliclazide on the Incretin Effect and Indices of Beta-cell Function. J Clin Endocrinol Metab 2021; 106:2036-2046. [PMID: 33693776 PMCID: PMC8692237 DOI: 10.1210/clinem/dgab151] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Indexed: 12/02/2022]
Abstract
AIMS/HYPOTHESIS Studies in permanent neonatal diabetes suggest that sulphonylureas lower blood glucose without causing hypoglycemia, in part by augmenting the incretin effect. This mechanism has not previously been attributed to sulphonylureas in patients with type 2 diabetes (T2DM). We therefore aimed to evaluate the impact of low-dose gliclazide on beta-cell function and incretin action in patients with T2DM. METHODS Paired oral glucose tolerance tests and isoglycemic infusions were performed to evaluate the difference in the classical incretin effect in the presence and absence of low-dose gliclazide in 16 subjects with T2DM (hemoglobin A1c < 64 mmol/mol, 8.0%) treated with diet or metformin monotherapy. Beta-cell function modeling was undertaken to describe the relationship between insulin secretion and glucose concentration. RESULTS A single dose of 20 mg gliclazide reduced mean glucose during the oral glucose tolerance test from 12.01 ± 0.56 to 10.82 ± 0.5mmol/l [P = 0.0006; mean ± standard error of the mean (SEM)]. The classical incretin effect was augmented by 20 mg gliclazide, from 35.5% (lower quartile 27.3, upper quartile 61.2) to 54.99% (34.8, 72.8; P = 0.049). Gliclazide increased beta-cell glucose sensitivity by 46% [control 22.61 ± 3.94, gliclazide 33.11 ± 7.83 (P = 0.01)] as well as late-phase incretin potentiation [control 0.92 ± 0.05, gliclazide 1.285 ± 0.14 (P = 0.038)]. CONCLUSIONS/INTERPRETATION Low-dose gliclazide reduces plasma glucose in response to oral glucose load, with concomitant augmentation of the classical incretin effect. Beta-cell modeling shows that low plasma concentrations of gliclazide potentiate late-phase insulin secretion and increase glucose sensitivity by 50%. Further studies are merited to explore whether low-dose gliclazide, by enhancing incretin action, could effectively lower blood glucose without risk of hypoglycemia.
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Affiliation(s)
- Ruth L M Cordiner
- Division of Population Health and Genomics, School of Medicine, University of Dundee, UK
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Tura
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, UK
- Correspondence: Professor Ewan Pearson, Head of Division, Population Health & Genomics, School of Medicine, University of Dundee, DD1 9SY, UK.
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14
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Kahleova H, McCann J, Alwarith J, Rembert E, Tura A, Holubkov R, Barnard ND. A plant-based diet in overweight adults in a 16-week randomized clinical trial: The role of dietary acid load. Clin Nutr ESPEN 2021; 44:150-158. [PMID: 34330460 DOI: 10.1016/j.clnesp.2021.05.015] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/02/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Evidence suggests that changes in dietary acid load may influence body weight, body composition, and insulin sensitivity. METHODS Participants (n = 244) were randomly assigned to an intervention (vegan) (n = 122) or control group (n = 122) for 16 weeks. Before and after the intervention period, body composition was measured by dual X-ray absorptiometry. Insulin resistance was assessed with the Homeostasis Model Assessment (HOMA-IR) index and predicted insulin sensitivity index (PREDIM). Repeated measure ANOVA was used for statistical analysis. RESULTS Potential Renal Acid Load (PRAL) and Net Endogenous Acid Production (NEAP) decreased significantly in the vegan group with no change in the control group (treatment effect -24.7 mEq/day [95% CI -30.2 to -19.2]; p < 0.001; and -23.8 mEq/day [95% CI -29.6 to -18.0]; p < 0.001, respectively). Body weight decreased by 6.4 kg in the vegan group, compared with 0.5 kg in the control group (treatment effect -5.9 kg [95% CI -6.8 to -5.0]; Gxt, p < 0.001), largely due to a reduction in fat mass and visceral fat. HOMA-IR index decreased and PREDIM increased in the vegan group. After adjustment for energy intake, changes in PRAL and NEAP correlated positively with changes in body weight (r = +0.37; p < 0.001; and r = +0.37; p < 0.001, respectively), fat mass (r = +0.32; p < 0.001; and r = +0.32; p < 0.001, respectively), visceral fat (r = +0.19; p = 0.006; and r = +0.15; p = 0.03, respectively), and HOMA (r = +0.17; p = 0.02; and r = +0.20; p = 0.006, respectively), and negatively with changes in PREDIM (r = -0.22; p = 0.002; and r = -0.27; p < 0.001, respectively). CONCLUSION Dietary acid load as part of a plant-based diet was associated with changes in body weight, body composition, and insulin sensitivity, independent of energy intake. Mechanistic explanations suggest that the relationship may be causal. TRIAL REGISTRATION ClinicalTrials.gov number, NCT03698955.
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Affiliation(s)
- Hana Kahleova
- Physicians Committee for Responsible Medicine, Washington, DC, USA.
| | - James McCann
- Physicians Committee for Responsible Medicine, Washington, DC, USA
| | - Jihad Alwarith
- Physicians Committee for Responsible Medicine, Washington, DC, USA
| | - Emilie Rembert
- Physicians Committee for Responsible Medicine, Washington, DC, USA
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padua, Italy
| | | | - Neal D Barnard
- Physicians Committee for Responsible Medicine, Washington, DC, USA; Adjunct Faculty, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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15
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Morettini M, Burattini L, Göbl C, Pacini G, Ahrén B, Tura A. Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test. Front Endocrinol (Lausanne) 2021; 12:611147. [PMID: 33828527 PMCID: PMC8020816 DOI: 10.3389/fendo.2021.611147] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 01/26/2021] [Indexed: 01/29/2023] Open
Abstract
Glucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear. To gain insight into this, we aimed to develop a mathematical model of the glucagon kinetics during an oral glucose tolerance test, which is sufficiently simple to be used in the clinical practice. The proposed model included two first-order differential equations -one describing glucagon and the other describing C-peptide in a compartment remote from plasma - and yielded a parameter of possible clinical relevance (i.e., SGLUCA(t), glucagon-inhibition sensitivity to glucose-induced insulin secretion). Model was validated on mean glucagon data derived from the scientific literature, yielding values for SGLUCA(t) ranging from -15.03 to 2.75 (ng of glucagon·nmol of C-peptide-1). A further validation on a total of 100 virtual subjects provided reliable results (mean residuals between -1.5 and 1.5 ng·L-1) and a negative significant linear correlation (r = -0.74, p < 0.0001, 95% CI: -0.82 - -0.64) between SGLUCA(t) and the ratio between the areas under the curve of suprabasal remote C-peptide and glucagon. Model reliability was also proven by the ability to capture different patterns in glucagon kinetics. In conclusion, the proposed model reliably reproduces glucagon kinetics and is characterized by sufficient simplicity to be possibly used in the clinical practice, for the estimation in the single individual of some glucagon-related parameters.
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Affiliation(s)
- Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
- *Correspondence: Micaela Morettini,
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Christian Göbl
- Division of Obstetrics and Feto-Maternal Medicine, Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Giovanni Pacini
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
| | - Bo Ahrén
- Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
| | - Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
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Mari A, Tura A, Grespan E, Bizzotto R. Mathematical Modeling for the Physiological and Clinical Investigation of Glucose Homeostasis and Diabetes. Front Physiol 2020; 11:575789. [PMID: 33324238 PMCID: PMC7723974 DOI: 10.3389/fphys.2020.575789] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 11/04/2020] [Indexed: 12/21/2022] Open
Abstract
Mathematical modeling in the field of glucose metabolism has a longstanding tradition. The use of models is motivated by several reasons. Models have been used for calculating parameters of physiological interest from experimental data indirectly, to provide an unambiguous quantitative representation of pathophysiological mechanisms, to determine indices of clinical usefulness from simple experimental tests. With the growing societal impact of type 2 diabetes, which involves the disturbance of the glucose homeostasis system, development and use of models in this area have increased. Following the approaches of physiological and clinical investigation, the focus of the models has spanned from representations of whole body processes to those of cells, i.e., from in vivo to in vitro research. Model-based approaches for linking in vivo to in vitro research have been proposed, as well as multiscale models merging the two areas. The success and impact of models has been variable. Two kinds of models have received remarkable interest: those widely used in clinical applications, e.g., for the assessment of insulin sensitivity and β-cell function and some models representing specific aspects of the glucose homeostasis system, which have become iconic for their efficacy in describing clearly and compactly key physiological processes, such as insulin secretion from the pancreatic β cells. Models are inevitably simplified and approximate representations of a physiological system. Key to their success is an appropriate balance between adherence to reality, comprehensibility, interpretative value and practical usefulness. This has been achieved with a variety of approaches. Although many models concerning the glucose homeostasis system have been proposed, research in this area still needs to address numerous issues and tackle new opportunities. The mathematical representation of the glucose homeostasis processes is only partial, also because some mechanisms are still only partially understood. For in vitro research, mathematical models still need to develop their potential. This review illustrates the problems, approaches and contribution of mathematical modeling to the physiological and clinical investigation of glucose homeostasis and diabetes, focusing on the most relevant and stimulating models.
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Affiliation(s)
- Andrea Mari
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Andrea Tura
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Eleonora Grespan
- Institute of Neuroscience, National Research Council, Padua, Italy
| | - Roberto Bizzotto
- Institute of Neuroscience, National Research Council, Padua, Italy
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Tura A, Göbl C, Morettini M, Burattini L, Kautzky-Willer A, Pacini G. Insulin clearance is altered in women with a history of gestational diabetes progressing to type 2 diabetes. Nutr Metab Cardiovasc Dis 2020; 30:1272-1280. [PMID: 32513580 DOI: 10.1016/j.numecd.2020.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 03/27/2020] [Accepted: 04/06/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND AND AIMS Insulin clearance is a relevant process in glucose homeostasis. In this observational study, we aimed to assess insulin clearance (ClINS) in women with former gestational diabetes (fGDM) both early after delivery and after a follow-up. METHODS AND RESULTS We analysed 59 fGDM women, and 16 women not developing GDM (CNT). All women underwent an oral glucose tolerance test (OGTT) yearly, and an insulin-modified intravenous glucose tolerance test (IVGTT) at baseline and at follow-up end (until 7 years). Both IVGTT and OGTT ClINS was assessed as insulin secretion to plasma insulin ratio. We also defined IVGTT first (0-10 min) and second phase (10-180 min) ClINS. We found that 14 fGDM women progressed to type 2 diabetes (PROG), whereas 45 women remained diabetes-free (NONPROG). At baseline, IVGTT ClINS showed alterations in PROG, especially in second phase (0.88 ± 0.10 l·min-1 in PROG, 0.60 ± 0.06 in NONPROG, 0.54 ± 0.07 in CNT, p ≤ 0.03). Differences in ClINS were not found from OGTT. Cox regression analysis showed second phase ClINS as significant type 2 diabetes predictor (hazard ratio = 1.90, 95% confidence interval 1.09-3.30, p = 0.02). CONCLUSION This study showed that insulin clearance derived from an insulin-modified IVGTT is notably altered in women with history of GDM progressing towards type 2 diabetes.
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Affiliation(s)
- Andrea Tura
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy.
| | - Christian Göbl
- Department of Obstetrics and Gynecology, Division of Obstetrics and Feto-Maternal Medicine, Medical University of Vienna, Vienna, Austria
| | - Micaela Morettini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Laura Burattini
- Department of Information Engineering, Università Politecnica delle Marche, Ancona, Italy
| | - Alexandra Kautzky-Willer
- Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Giovanni Pacini
- Metabolic Unit, CNR Institute of Neuroscience, Padova, Italy
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Papaetis GS. Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence. Curr Diabetes Rev 2020; 16:699-715. [PMID: 31886752 DOI: 10.2174/1573399816666191230113446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. INTRODUCTION The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. METHODS Pubmed and Google databases have been thoroughly searched and relevant studies were selected. RESULTS This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. CONCLUSION Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.
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Affiliation(s)
- Georgios S Papaetis
- Internal Medicine and Diabetes Clinic, Eleftherios Venizelos Avenue 62, Paphos, Cyprus
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Astiarraga B, Chueire VB, Souza AL, Pereira-Moreira R, Monte Alegre S, Natali A, Tura A, Mari A, Ferrannini E, Muscelli E. Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes. Diabetologia 2018; 61:1829-1837. [PMID: 29732475 DOI: 10.1007/s00125-018-4633-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Accepted: 04/04/2018] [Indexed: 01/08/2023]
Abstract
AIMS/HYPOTHESIS Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans. METHODS Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3 h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (β-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); the oral glucose sensitivity index was used to estimate insulin sensitivity. RESULTS Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m2 on OGTT and from 29 nmol/m2 [26] to 57 nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). β-GS, PGLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change β-GS, PINCR, PGLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes. CONCLUSIONS/INTERPRETATION Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.
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Affiliation(s)
- Brenno Astiarraga
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Valéria B Chueire
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | - Aglécio L Souza
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | | | - Sarah Monte Alegre
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | | | - Ele Ferrannini
- CNR Institute of Clinical Physiology, Via Savi, 10, 56100, Pisa, Italy.
| | - Elza Muscelli
- Department of Internal Medicine, University of Campinas, Campinas, Brazil
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20
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Yang YS, Lim MH, Lee SO, Roh E, Ahn CH, Kwak SH, Cho YM, Kim S, Mari A, Park KS, Jung HS. Fimasartan increases glucose-stimulated insulin secretion in patients with type 2 diabetes and hypertension compared with amlodipine. Diabetes Obes Metab 2018; 20:1670-1677. [PMID: 29546730 DOI: 10.1111/dom.13282] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 02/21/2018] [Accepted: 03/04/2018] [Indexed: 12/22/2022]
Abstract
AIM To study the effects of angiotensin receptor blockers (ARBs) on insulin secretion in hypertensive patients with type 2 diabetes. MATERIALS AND METHODS A total of 41 patients were enrolled in this open-label, active comparator-controlled, crossover study. After a 2-week run-in period with amlodipine, the participants were assigned to receive either fimasartan (60-120 mg daily) or amlodipine (5-10 mg daily) for 16 weeks. Thereafter, they were treated with the other drug for another 16 weeks. Physical examinations and laboratory tests were performed before and after each treatment. RESULTS Blood pressure, glycated haemoglobin and oral glucose tolerance test (OGTT) values were similar with each treatment. Fimasartan treatment significantly increased median (range) homeostatic assessment of β-cell function values (49.9 [22.5-174.4] vs 46.9 [15.6-148.0]), area under the curve of insulin during OGTT (27 284 [9501-94 525] vs 26 818 [8112-76 704] pmol/L × min), insulinogenic index at 60 minutes (19.7 [3.0-131.2] vs 15.0 [2.4-103.8] pmol/mmol) and at 120 minutes (19.1 [1.9-85.5] vs 12.6 [-4.3-178.8] pmol/mmol) compared with those with amlodipine (all P < .05); however, acute insulin response and insulin resistance indices were similar for both agents. CONCLUSIONS Compared with amlodipine, fimasartan increased late-phase glucose-stimulated insulin secretion in patients with type 2 diabetes and hypertension. This finding suggests that ARBs would be more beneficial in such patients compared with other classes of anti-hypertensives.
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Affiliation(s)
- Ye Seul Yang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Min Hyuk Lim
- Departments of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seong Ok Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Eun Roh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chang Ho Ahn
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Sungwan Kim
- Departments of Biomedical Engineering, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hye Seung Jung
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Innovative Research Institute for Cell Therapy, Seoul National University Hospital, Seoul, Republic of Korea
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21
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GLP-1 response to sequential mixed meals: influence of insulin resistance. Clin Sci (Lond) 2017; 131:2901-2910. [PMID: 29097626 DOI: 10.1042/cs20171409] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 10/26/2017] [Accepted: 11/01/2017] [Indexed: 12/25/2022]
Abstract
Previous work has shown that potentiation of insulin release is impaired in non-diabetic insulin resistance; we tested the hypothesis that this defect may be related to altered glucagon-like peptide-1 (GLP-1) release. On consecutive days, 82 non-diabetic individuals, classified as insulin sensitive (IS, n=41) or insulin resistant (IR, n=41) by the euglycaemic clamp, were given two sequential mixed meals with standard (75 g, LCD) or double (150 g, HCD) carbohydrate content. Plasma glucose, insulin, C-peptide, non-esterified fatty acids (NEFA) and GLP-1 concentrations were measured; β-cell function (glucose sensitivity and potentiation) was resolved by mathematical modelling. Fasting GLP-1 levels were higher in IR than IS (by 15%, P=0.006), and reciprocally related to insulin sensitivity after adjustment for sex, age, fat mass, fasting glucose or insulin concentrations. Mean postprandial GLP-1 responses were tightly correlated with fasting GLP-1, were higher for the second than the first meal, and higher in IR than IS subjects but only with LCD. In contrast, incremental GLP-1 responses were higher during (i) the second than the first meal, (ii) on HCD than LCD, and (iii) significantly smaller in IR than IS independently of meal and load. Potentiation of insulin release was markedly reduced in IR vs IS across meal and carbohydrate loading. In the whole dataset, incremental GLP-1 was directly related to potentiation, and both were inversely related to mean NEFA concentrations. We conclude that (a) raised GLP-1 tone may be inherently linked with a reduced GLP-1 response and (b) defective post-meal GLP-1 response may be one mechanism for impaired potentiation of insulin release in insulin resistance.
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22
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Tura A, Bagger JI, Ferrannini E, Holst JJ, Knop FK, Vilsbøll T, Mari A. Impaired beta cell sensitivity to incretins in type 2 diabetes is insufficiently compensated by higher incretin response. Nutr Metab Cardiovasc Dis 2017; 27:1123-1129. [PMID: 29162361 DOI: 10.1016/j.numecd.2017.10.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/15/2017] [Accepted: 10/05/2017] [Indexed: 11/20/2022]
Abstract
BACKGROUND AND AIMS The incretin effect is impaired in type 2 diabetes (T2D), but the underlying mechanisms are only partially understood. We investigated the relationships between the time course of the incretin effect and that of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) during oral glucose tolerance tests (OGTTs), thereby estimating incretin sensitivity of the beta cell, and its associated factors. METHODS AND RESULTS Eight patients with T2D and eight matched subjects with normal glucose tolerance (NGT) received 25, 75, and 125 g OGTTs and corresponding isoglycemic glucose infusions (IIGI). The time course of the incretin effect, representing potentiation of insulin secretion by incretins (PINCR), was determined by mathematical modelling as the time-dependent fold increase in insulin secretion during OGTT compared to IIGI. The time course of PINCR was correlated with that of both GIP and GLP-1 in each subject (median r = 0.67 in NGT and 0.45 in T2D). We calculated an individual beta cell sensitivity to incretins (SINCR) using a weighted average of GIP and GLP-1 (pooled incretin concentration, PIC), as the slope of the relationship between PINCR and PIC. SINCR was reduced in T2D (p < 0.01). In the whole group, mean PIC, GIP and GLP-1 concentrations during the OGTT were inversely correlated with SINCR, but T2D had lower PIC, GIP and GLP-1 levels at the same SINCR (p < 0.05). CONCLUSION Relative incretin insensitivity is partly compensated for by higher incretin secretory responses. However, T2D shows both impairment in incretin sensitivity and abnormal compensation by incretin secretion.
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Affiliation(s)
- A Tura
- CNR Institute of Neuroscience, Padova, Italy
| | - J I Bagger
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - E Ferrannini
- Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy; CNR Institute of Clinical Physiology, Pisa, Italy
| | - J J Holst
- The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - F K Knop
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; The NNF Center for Basic Metabolic Research, Department of Biomedical Sciences, 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
| | - T Vilsbøll
- Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - A Mari
- CNR Institute of Neuroscience, Padova, Italy.
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23
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A system model of the effects of exercise on plasma Interleukin-6 dynamics in healthy individuals: Role of skeletal muscle and adipose tissue. PLoS One 2017; 12:e0181224. [PMID: 28704555 PMCID: PMC5507524 DOI: 10.1371/journal.pone.0181224] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 06/27/2017] [Indexed: 12/25/2022] Open
Abstract
Interleukin-6 (IL-6) has been recently shown to play a central role in glucose homeostasis, since it stimulates the production and secretion of Glucagon-like Peptide-1 (GLP-1) from intestinal L-cells and pancreas, leading to an enhanced insulin response. In resting conditions, IL-6 is mainly produced by the adipose tissue whereas, during exercise, skeletal muscle contractions stimulate a marked IL-6 secretion as well. Available mathematical models describing the effects of exercise on glucose homeostasis, however, do not account for this IL-6 contribution. This study aimed at developing and validating a system model of exercise’s effects on plasma IL-6 dynamics in healthy humans, combining the contributions of both adipose tissue and skeletal muscle. A two-compartment description was adopted to model plasma IL-6 changes in response to oxygen uptake’s variation during an exercise bout. The free parameters of the model were estimated by means of a cross-validation procedure performed on four different datasets. A low coefficient of variation (<10%) was found for each parameter and the physiologically meaningful parameters were all consistent with literature data. Moreover, plasma IL-6 dynamics during exercise and post-exercise were consistent with literature data from exercise protocols differing in intensity, duration and modality. The model successfully emulated the physiological effects of exercise on plasma IL-6 levels and provided a reliable description of the role of skeletal muscle and adipose tissue on the dynamics of plasma IL-6. The system model here proposed is suitable to simulate IL-6 response to different exercise modalities. Its future integration with existing models of GLP-1-induced insulin secretion might provide a more reliable description of exercise’s effects on glucose homeostasis and hence support the definition of more tailored interventions for the treatment of type 2 diabetes.
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24
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Marchetti L, Reali F, Dauriz M, Brangani C, Boselli L, Ceradini G, Bonora E, Bonadonna RC, Priami C. A Novel Insulin/Glucose Model after a Mixed-Meal Test in Patients with Type 1 Diabetes on Insulin Pump Therapy. Sci Rep 2016; 6:36029. [PMID: 27824066 PMCID: PMC5099899 DOI: 10.1038/srep36029] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 10/10/2016] [Indexed: 11/30/2022] Open
Abstract
Current closed-loop insulin delivery methods stem from sophisticated models of the glucose-insulin (G/I) system, mostly based on complex studies employing glucose tracer technology. We tested the performance of a new minimal model (GLUKINSLOOP 2.0) of the G/I system to characterize the glucose and insulin dynamics during multiple mixed meal tests (MMT) of different sizes in patients with type 1 diabetes (T1D) on insulin pump therapy (continuous subcutaneous insulin infusion, CSII). The GLUKINSLOOP 2.0 identified the G/I system, provided a close fit of the G/I time-courses and showed acceptable reproducibility of the G/I system parameters in repeated studies of identical and double-sized MMTs. This model can provide a fairly good and reproducible description of the G/I system in T1D patients on CSII, and it may be applied to create a bank of “virtual” patients. Our results might be relevant at improving the architecture of upcoming closed-loop CSII systems.
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Affiliation(s)
- Luca Marchetti
- The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto (TN), Italy
| | - Federico Reali
- The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto (TN), Italy.,Department of Mathematics, University of Trento, Trento, Italy
| | - Marco Dauriz
- Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy
| | - Corinna Brangani
- Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy
| | - Linda Boselli
- Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy
| | - Giulia Ceradini
- Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy
| | - Enzo Bonora
- Department of Medicine, Section of Endocrinology, University of Verona School of Medicine, Verona, Italy.,Division of Endocrinology and Metabolic Diseases, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Riccardo C Bonadonna
- Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.,Division of Endocrinology, Azienda Ospedaliera Universitaria of Parma, Italy
| | - Corrado Priami
- The Microsoft Research - University of Trento Centre for Computational and Systems Biology (COSBI), Rovereto (TN), Italy.,Department of Mathematics, University of Trento, Trento, Italy
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Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence. Int J Mol Sci 2016; 17:ijms17081223. [PMID: 27483245 PMCID: PMC5000621 DOI: 10.3390/ijms17081223] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 07/16/2016] [Accepted: 07/25/2016] [Indexed: 02/07/2023] Open
Abstract
An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications.
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26
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Vogt JA, Domzig C, Wabitsch M, Denzer C. Prehepatic secretion and disposal of insulin in obese adolescents as estimated by three-hour, eight-sample oral glucose tolerance tests. Am J Physiol Endocrinol Metab 2016; 311:E82-94. [PMID: 27143555 DOI: 10.1152/ajpendo.00455.2014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Accepted: 04/25/2016] [Indexed: 01/10/2023]
Abstract
The body compensates for early-stage insulin resistance by increasing insulin secretion. A reliable and easy-to-use mathematical assessment of insulin secretion and disposal could be a valuable tool for identifying patients at risk for the development of type 2 diabetes. Because the pathophysiology of insulin resistance is incompletely understood, assessing insulin metabolism with minimal assumptions regarding its metabolic regulation is a major challenge. To assess insulin secretion and indexes of insulin disposal, our marginalized and regularized absorption approach (MRA) was applied to a sparse sampling oral glucose tolerance test (OGTT) protocol measuring the insulin and C-peptide concentrations. Identifiability and potential bias of metabolic parameters were estimated from published data with dense sampling. The MRA was applied to OGTT data from 135 obese adolescents to demonstrate its clinical applicability. Individual prehepatic basal and dynamic insulin secretion and clearance levels were determined with a precision and accuracy greater than 10% of the nominal value. The intersubject variability in these parameters was approximately four times higher than the intrasubject variability, and there was a strong negative correlation between prehepatic secretion and plasma clearance of insulin. MRA-based analysis provides reliable estimates of insulin secretion and clearance, thereby enabling detailed glucose homeostasis characterization based on restricted datasets that are obtainable during routine patient care.
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Affiliation(s)
- Josef A Vogt
- Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Universitätsklinikum Ulm, Ulm, Germany; and
| | - Christian Domzig
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Christian Denzer
- Division of Pediatric Endocrinology and Diabetes, Interdisciplinary Obesity Unit, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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27
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Natalicchio A, Biondi G, Marrano N, Labarbuta R, Tortosa F, Spagnuolo R, D'Oria R, Carchia E, Leonardini A, Cignarelli A, Perrini S, Laviola L, Giorgino F. Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response. Endocrinology 2016; 157:2243-58. [PMID: 27035653 DOI: 10.1210/en.2015-2003] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.
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Affiliation(s)
- Annalisa Natalicchio
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Giuseppina Biondi
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Nicola Marrano
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Rossella Labarbuta
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Federica Tortosa
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Rosaria Spagnuolo
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Rossella D'Oria
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Emanuele Carchia
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Anna Leonardini
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Angelo Cignarelli
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Sebastio Perrini
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Luigi Laviola
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation (A.N., G.B., N.M., R.L., F.T., R.S., R.D., A.L., A.C., S.P., L.L., F.G.), Section of Internal Medicine, Endocrinology, Andrology, and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; and IRGS Biogem (E.C.), I-83031 Ariano Irpino, Avellino, Italy
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28
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Nyman E, Rozendaal YJW, Helmlinger G, Hamrén B, Kjellsson MC, Strålfors P, van Riel NAW, Gennemark P, Cedersund G. Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes. Interface Focus 2016; 6:20150075. [PMID: 27051506 DOI: 10.1098/rsfs.2015.0075] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We are currently in the middle of a major shift in biomedical research: unprecedented and rapidly growing amounts of data may be obtained today, from in vitro, in vivo and clinical studies, at molecular, physiological and clinical levels. To make use of these large-scale, multi-level datasets, corresponding multi-level mathematical models are needed, i.e. models that simultaneously capture multiple layers of the biological, physiological and disease-level organization (also referred to as quantitative systems pharmacology-QSP-models). However, today's multi-level models are not yet embedded in end-usage applications, neither in drug research and development nor in the clinic. Given the expectations and claims made historically, this seemingly slow adoption may seem surprising. Therefore, we herein consider a specific example-type 2 diabetes-and critically review the current status and identify key remaining steps for these models to become mainstream in the future. This overview reveals how, today, we may use models to ask scientific questions concerning, e.g., the cellular origin of insulin resistance, and how this translates to the whole-body level and short-term meal responses. However, before these multi-level models can become truly useful, they need to be linked with the capabilities of other important existing models, in order to make them 'personalized' (e.g. specific to certain patient phenotypes) and capable of describing long-term disease progression. To be useful in drug development, it is also critical that the developed models and their underlying data and assumptions are easily accessible. For clinical end-usage, in addition, model links to decision-support systems combined with the engagement of other disciplines are needed to create user-friendly and cost-efficient software packages.
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Affiliation(s)
- Elin Nyman
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; CVMD iMed DMPK AstraZeneca R&D, Gothenburg, Sweden
| | - Yvonne J W Rozendaal
- Department of Biomedical Engineering , Eindhoven University of Technology , Eindhoven , The Netherlands
| | - Gabriel Helmlinger
- Quantitative Clinical Pharmacology, AstraZeneca , Pharmaceuticals LP, Waltham, MA , USA
| | - Bengt Hamrén
- Quantitative Clinical Pharmacology , AstraZeneca , Gothenburg , Sweden
| | - Maria C Kjellsson
- Department of Pharmaceutical Biosciences , Uppsala University , Uppsala , Sweden
| | - Peter Strålfors
- Department of Clinical and Experimental Medicine , Linköping University , Linköping , Sweden
| | - Natal A W van Riel
- Department of Biomedical Engineering , Eindhoven University of Technology , Eindhoven , The Netherlands
| | | | - Gunnar Cedersund
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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29
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Dalla Man C, Micheletto F, Sathananthan M, Vella A, Cobelli C. Model-Based Quantification of Glucagon-Like Peptide-1-Induced Potentiation of Insulin Secretion in Response to a Mixed Meal Challenge. Diabetes Technol Ther 2016; 18:39-46. [PMID: 26756104 PMCID: PMC4717506 DOI: 10.1089/dia.2015.0146] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) is a powerful insulin secretagogue that is secreted in response to meal ingestion. The ability to quantify the effect of GLP-1 on insulin secretion could provide insights into the pathogenesis and treatment of diabetes. We used a modification of a model of GLP-1 action on insulin secretion using data from a hyperglycemic clamp with concomitant GLP-1 infusion. We tested this model using data from a mixed meal test (MMT), thereby measuring GLP-1-induced potentiation of insulin secretion in response to a meal. MATERIALS AND METHODS The GLP-1 model is based on the oral C-peptide minimal model and assumes that over-basal insulin secretion depends linearly on GLP-1 concentration through the parameter Π, representing the β-cell sensitivity to GLP-1. The model was tested on 62 subjects across the spectrum of glucose tolerance (age, 53 ± 1 years; body mass index, 29.7 ± 0.6 kg/m(2)) studied with an MMT and provided a precise estimate of both β-cell responsivity and Π indices. By combining Π with a measure of L-cell responsivity to glucose, one obtains a potentiation index (PI) (i.e., a measure of the L-cell's function in relation to prevailing β-cell sensitivity to GLP-1). RESULTS Model-based measurement of GLP-1-induced insulin secretion demonstrates that the PI is significantly reduced in people with impaired glucose tolerance, compared with those with normal glucose tolerance. CONCLUSIONS We describe a model that can quantitate the GLP-1-based contribution to insulin secretion in response to meal ingestion. This methodology will allow a better understanding of β-cell function at various stages of glucose tolerance.
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Affiliation(s)
- Chiara Dalla Man
- Department of Information Engineering, University of Padua, Padua, Italy
| | | | - Matheni Sathananthan
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Adrian Vella
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Claudio Cobelli
- Department of Information Engineering, University of Padua, Padua, Italy
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Alsalim W, Tura A, Pacini G, Omar B, Bizzotto R, Mari A, Ahrén B. Mixed meal ingestion diminishes glucose excursion in comparison with glucose ingestion via several adaptive mechanisms in people with and without type 2 diabetes. Diabetes Obes Metab 2016; 18:24-33. [PMID: 26354383 DOI: 10.1111/dom.12570] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 08/09/2015] [Accepted: 08/28/2015] [Indexed: 12/24/2022]
Abstract
AIMS To study the integrative impact of macronutrients on postprandial glycaemia, β-cell function, glucagon and incretin hormones in humans. METHODS Macronutrients were ingested alone (glucose 330 kcal, protein 110 kcal or fat 110 kcal) or together (550 kcal) by healthy subjects (n = 18) and by subjects with drug-naïve type 2 diabetes (T2D; n = 18). β-cell function and insulin clearance were estimated by modelling glucose, insulin and C-peptide data. Secretion of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were measured, and paracetamol was administered to estimate gastric emptying. RESULTS In both groups, the mixed-meal challenge diminished glucose excursion compared with glucose challenge alone, and insulin levels, but not C-peptide levels, rose more than after the mixed meal than after glucose alone. β-cell function was augmented, insulin clearance was reduced and glucagon levels were higher after the mixed meal compared with glucose alone. GLP-1 and GIP levels increased after all challenges and GIP secretion was markedly higher after the mixed meal than after glucose alone. The appearance of paracetamol was delayed after the mixed-meal challenge compared with glucose alone. CONCLUSIONS Adding protein and fat macronutrients to glucose in a mixed meal diminished glucose excursion. This occurred in association with increased β-cell function, reduced insulin clearance, delayed gastric emptying and augmented glucagon and GIP secretion. This suggests that the macronutrient composition regulates glycaemia through both islet and extra-islet mechanisms in both healthy subjects and in subjects with T2D.
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Affiliation(s)
- W Alsalim
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - A Tura
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - G Pacini
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - B Omar
- Department of Clinical Sciences, Lund University, Lund, Sweden
| | - R Bizzotto
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - A Mari
- Institute of Neuroscience, National Research Council, Padova, Italy
| | - B Ahrén
- Department of Clinical Sciences, Lund University, Lund, Sweden
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31
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Hurwitz BE, Schneiderman N, Marks JB, Mendez AJ, Gonzalez A, Llabre MM, Smith SR, Bizzotto R, Santini E, Manca ML, Skyler JS, Mari A, Ferrannini E. Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance. Diabetes 2015; 64:2550-9. [PMID: 25754957 PMCID: PMC4477346 DOI: 10.2337/db15-0106] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/02/2015] [Indexed: 12/23/2022]
Abstract
High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [n = 64] or insulin-resistant [IR] [n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.
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Affiliation(s)
- Barry E Hurwitz
- Behavioral Medicine Research Center, University of Miami, Miami, FL Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Miami, FL Department of Psychology, University of Miami, Coral Gables, FL
| | - Neil Schneiderman
- Behavioral Medicine Research Center, University of Miami, Miami, FL Department of Psychology, University of Miami, Coral Gables, FL
| | - Jennifer B Marks
- Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Miami, FL
| | - Armando J Mendez
- Behavioral Medicine Research Center, University of Miami, Miami, FL Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Miami, FL
| | - Alex Gonzalez
- Behavioral Medicine Research Center, University of Miami, Miami, FL
| | - Maria M Llabre
- Behavioral Medicine Research Center, University of Miami, Miami, FL Department of Psychology, University of Miami, Coral Gables, FL
| | - Steven R Smith
- Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL
| | - Roberto Bizzotto
- National Research Council Institute of Biomedical Engineering, Padua, Italy
| | - Eleonora Santini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Maria Laura Manca
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Jay S Skyler
- Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Miami, FL
| | - Andrea Mari
- National Research Council Institute of Biomedical Engineering, Padua, Italy
| | - Ele Ferrannini
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy National Research Council Institute of Clinical Physiology, Pisa, Italy
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32
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McCue ME, Geor RJ, Schultz N. Equine Metabolic Syndrome: A Complex Disease Influenced by Genetics and the Environment. J Equine Vet Sci 2015. [DOI: 10.1016/j.jevs.2015.03.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Sato Y, Oka R, Nakasone Y, Katakura M, Yamauchi K, Aizawa T. Impact of one-hour postchallenge glucose on the relationship between insulin sensitivity and secretion. Endocr J 2015; 62:573-83. [PMID: 26052138 DOI: 10.1507/endocrj.ej15-0122] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The impact of postchallenge glucose on the relationship between insulin sensitivity (SI) and secretion (β) is unknown. We analyzed data from 2,264 health examinees (male/female 1,524/740, median age 54 yrs) with normal glucose tolerance (NGT, n = 1,623), non-diabetic hyperglycemia (NDH, n = 555), or diabetes (DM, n = 86) using OGTT-derived indices of SI (insulin sensitivity index [ISI]-Matsuda, 1/HOMA-IR, and 1/fasting IRI) and β (δIRI0-30/δPG0-30, and Stumvoll 1st [Stumvoll-1] and 2nd [Stumvoll-2] phases). The combination of 1/HOMA-IR and Stumvoll-1 recapitulated the hyperbolic SI-β relationship with the slope of the fitted line -1.000 in NGT subjects, and therefore it was utilized in the following analysis of the SI-β correlation. In multiple regression analysis of the relationship between SI and β, an independent correlation was found for 1 h-plasma glucose (PG; PG60) but not for 2 h-PG. When the NGT subjects were grouped by PG60 quartile (Q), the fitted line was flat in Q1 but progressively steeper from Q2 to Q4, with a slope (95%CI) of -0.663 (-0.726~-0.605), -0.680 (-0.745~-0.622), -0.847 (-0.922~-0.779), and -1.259 (-1.370~-1.158) (P for trend < 0.05). The fitted line steepened further in the NDH and DM groups, with a slope of -1.545 and -1.915, respectively (P < 0.01 for the difference). The intercept of the fitted line for SI-β correlation was also progressively lower across the PG60 Q for NGT, NDH, and DM. In conclusion, using the 1/HOMA-IR-Stumvoll-1 pair for an analysis of the SI-β relationship, elevated PG60 was associated with steepening and downward shifting of the fitted line for the SI-β correlation. The finding suggests impaired beta cell function.
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Affiliation(s)
- Yuka Sato
- Diabetes Center, Aizawa Hospital, Matsumoto 390-8510, Japan
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Papaetis GS. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J Diabetes 2014; 5:817-834. [PMID: 25512784 PMCID: PMC4265868 DOI: 10.4239/wjd.v5.i6.817] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2014] [Revised: 09/10/2014] [Accepted: 11/10/2014] [Indexed: 02/05/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.
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35
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Ferrannini E, Mari A. β-Cell function in type 2 diabetes. Metabolism 2014; 63:1217-27. [PMID: 25070616 DOI: 10.1016/j.metabol.2014.05.012] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 05/09/2014] [Accepted: 05/25/2014] [Indexed: 01/09/2023]
Abstract
Different in vivo tests explore different aspects of β-cell function. Because intercorrelation of insulin secretion indices is modest, no single in vivo test allows β-cell function to be assessed with accuracy and specificity comparable to insulin sensitivity. Physiologically-based mathematical modeling is necessary to interpret insulin secretory responses in terms of relevant parameters of β-cell function. Models can be used to analyze intravenous glucose tests, but secretory responses to intravenous glucose may be paradoxical in subjects with diabetes. Use of oral glucose (or mixed meal) data may be preferable not only for simplicity but also for physiological interpretation. While the disposition index focuses on the relationship between insulin secretion and insulin resistance, secretion parameters reflecting the dynamic response to changing glucose levels over a time frame of minutes or hours--such as β-cell glucose sensitivity--are key to explain changes in glucose tolerance and are largely independent of insulin sensitivity. Pathognomonic of the β-cell defect of type 2 diabetes is a reduced glucose sensitivity, which is accompanied by normal or raised absolute insulin secretion rates--compensatory to the attendant insulin resistance--and impaired incretin-induced potentiation. As β-cell mass is frequently within the range of nondiabetic individuals, these defects are predominantly functional and potentially reversible. Any intervention, on lifestyle or with drugs, that improves glucose tolerance does so primarily through increased β-cell glucose sensitivity. So far, however, no intervention has proven unequivocally capable of modifying the natural course of β-cell dysfunction.
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Affiliation(s)
- Ele Ferrannini
- Department of Clinical & Experimental Medicine, University of Pisa, Italy.
| | - Andrea Mari
- C N R Institute of Biomedical Engineering, Padova, Italy
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