A glucose time in range of 70% attenuates the senescence-inducing and pro-inflammatory effects of hyperglycemia.
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| Názov: | A glucose time in range of 70% attenuates the senescence-inducing and pro-inflammatory effects of hyperglycemia. |
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| Autori: | La Grotta R; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138, Milan, Italy., Pellegrini V; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138, Milan, Italy., Carreras F; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138, Milan, Italy., Berra CC; Department of Endocrinology and Metabolic Diseases, IRCCS MultiMedica, Milan, Italy., Mužina K; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia., Jenko Bizjan B; Clinical Institute of Special Laboratory Diagnostics, University Children's Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia., Dovc K; Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, Ljubljana, Slovenia.; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia., Prattichizzo F; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138, Milan, Italy. francesco.prattichizzo@multimedica.it., Battelino T; Department of Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, Ljubljana, Slovenia.; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia., Ceriello A; IRCCS MultiMedica, Polo Scientifico e Tecnologico, Via Fantoli 16/15, 20138, Milan, Italy. |
| Zdroj: | Cardiovascular diabetology [Cardiovasc Diabetol] 2025 Nov 14; Vol. 24 (1), pp. 432. Date of Electronic Publication: 2025 Nov 14. |
| Spôsob vydávania: | Journal Article |
| Jazyk: | English |
| Informácie o časopise: | Publisher: BioMed Central Country of Publication: England NLM ID: 101147637 Publication Model: Electronic Cited Medium: Internet ISSN: 1475-2840 (Electronic) Linking ISSN: 14752840 NLM ISO Abbreviation: Cardiovasc Diabetol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: London : BioMed Central, [2002- |
| Výrazy zo slovníka MeSH: | Cellular Senescence*/drug effects , Hyperglycemia*/blood , Hyperglycemia*/metabolism , Hyperglycemia*/pathology , Inflammation Mediators*/metabolism , Inflammation Mediators*/blood , Blood Glucose*/metabolism , Inflammation*/blood , Inflammation*/metabolism , Diabetes Mellitus, Type 1*/blood , Endothelial Cells*/metabolism , Endothelial Cells*/drug effects , Endothelial Cells*/pathology, Humans ; Monocytes/metabolism ; Monocytes/drug effects ; Time Factors ; Cells, Cultured ; Male ; Cell Adhesion ; Adult ; Female ; Biomarkers/blood ; Human Umbilical Vein Endothelial Cells/metabolism ; Middle Aged |
| Abstrakt: | Competing Interests: Declarations. Ethics approval and consent to participate: Written informed consent was obtained from each participant using the principles of the Helsinki Declaration. The study protocol was approved by the Slovenian Ethical Committee (nr. 0120–6/2023/3). Consent for publication: Not applicable. Competing interests: T.B. served on advisory boards of Novo Nordisk, Sanofi, Eli Lilly, Boehringer Ingelheim, Medtronic, Abbott, and Indigo Diabetes. T.B. received honoraria for participating on the speakers’ bureau for Eli Lilly, Novo Nordisk, Medtronic, Abbott, Sanofi, Dexcom, Adventis, AstraZeneca, and Roche. T.B.’s institution has received research grant support and travel expenses from Abbott, GluSense, Medtronic, Novo Nordisk, Sanofi, Novartis, Sandoz, and Zealand Pharma. K.D. served on advisory boards for Medtronic and Novo Nordisk and speaker fees from Abbott, Dexcom, Eli Lilly, Novo Nordisk, Medtronic, and Pfizer. A.C. reports on being on Advisory Board, Consultancy, and Lectures: Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Hikamr Pharma, Guidotti, Eli Lilly, MSD, Merck, Novo, Roche Diagnostics, Sanofi, Servier, and SUN Pharma. No other potential conflicts of interest relevant to this article were reported. Background: The Time In Range (TIR) represents the amount of time spent by a given individual in the range close to normoglycemia, i.e. 70-180 mg/dl. On the basis of studies demonstrating an association of TIR with the incidence of diabetes complications, guidelines recommend a target of at least 70% of TIR for most people with diabetes. However, no study has explored the effect of variable degrees of TIR on molecular mechanisms relevant for the development of diabetes complications. Methods: We exposed endothelial cells and monocytes to increasing percentages of TIR, i.e. 50%, 70%, 85% by changing cell media twice a day as appropriate, as well as to constant normoglycemia (i.e. fixed 100 mg/dl of glucose for endothelial cells) and hyperglycemia (i.e. 500 mg/dl glucose), evaluating the development of senescence, of the associated pro-inflammatory response, and monocytes adhesion to endothelial cells as a functional assay. We then assessed the expression of a plethora of markers of senescence and inflammation at the mRNA level in peripheral blood mononuclear cells (PBMC)s derived from individuals with early (i.e. 1-year post-diagnosis) type 1 diabetes (T1D, n = 37), categorized according to the TIR (< or > 70%) observed in the previous 14 days, comparing the two groups through ANCOVA adjusted for HbA1c. As a confirmatory analysis, we also compared the expression of the same markers in people with Time Above Range (TAR), considered as the whole time above 180 mg/dl, ≥ vs < 30%. Correlations between TIR values and the expression of the same markers were tested through linear regression. Results: Constant hyperglycemia promoted the development of senescence in endothelial cells and induced inflammatory responses in both endothelial cells and monocytes, promoting also monocytes adhesion to endothelial cells. A TIR of 70%, but not of 50%, suppressed these effects while a TIR of 85% did not provide additional benefit. Data from people with T1D mirrored such results, as demonstrated by the higher expression of p16, a marker of senescence, and of IL-6, MCP-1, and CXCL1, three inflammatory mediators, in PBMCs from individuals with TIR < 70% and compared with those with TIR > 70%, independently of HbA1c. Similar results were obtained when comparing people with TAR ≥ vs < 30%. When considered as a continuous variable, TIR values were correlated with p16, IL-6, and CXCL1. Conclusions: A TIR above 70% is associated with attenuated pro-senescence and pro-inflammatory effects of hyperglycemia. These molecular results support the TIR target currently recommended by guidelines, especially for people with T1D. (© 2025. The Author(s).) |
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| Grant Information: | SG-2021-12372752 Ministero della Salute; Ricerca Corrente to IRCCS MultiMedica Ministero della Salute; J3-4528 Slovenian National Research Agency; P3-0343 Slovenian National Research Agency; J3-4521 The Slovenian Research and Innovation Agency |
| Contributed Indexing: | Keywords: Continuous glucose monitoring; Endothelial cells; Hyperglycemia; Inflammation; Monocytes; PBMC; Senescence; TAR; TIR; Type 1 diabetes |
| Substance Nomenclature: | 0 (Inflammation Mediators) 0 (Blood Glucose) 0 (Biomarkers) |
| Entry Date(s): | Date Created: 20251114 Date Completed: 20251115 Latest Revision: 20251117 |
| Update Code: | 20251117 |
| PubMed Central ID: | PMC12619397 |
| DOI: | 10.1186/s12933-025-02983-3 |
| PMID: | 41239371 |
| Databáza: | MEDLINE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Competing Interests: Declarations. Ethics approval and consent to participate: Written informed consent was obtained from each participant using the principles of the Helsinki Declaration. The study protocol was approved by the Slovenian Ethical Committee (nr. 0120–6/2023/3). Consent for publication: Not applicable. Competing interests: T.B. served on advisory boards of Novo Nordisk, Sanofi, Eli Lilly, Boehringer Ingelheim, Medtronic, Abbott, and Indigo Diabetes. T.B. received honoraria for participating on the speakers’ bureau for Eli Lilly, Novo Nordisk, Medtronic, Abbott, Sanofi, Dexcom, Adventis, AstraZeneca, and Roche. T.B.’s institution has received research grant support and travel expenses from Abbott, GluSense, Medtronic, Novo Nordisk, Sanofi, Novartis, Sandoz, and Zealand Pharma. K.D. served on advisory boards for Medtronic and Novo Nordisk and speaker fees from Abbott, Dexcom, Eli Lilly, Novo Nordisk, Medtronic, and Pfizer. A.C. reports on being on Advisory Board, Consultancy, and Lectures: Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Hikamr Pharma, Guidotti, Eli Lilly, MSD, Merck, Novo, Roche Diagnostics, Sanofi, Servier, and SUN Pharma. No other potential conflicts of interest relevant to this article were reported.<br />Background: The Time In Range (TIR) represents the amount of time spent by a given individual in the range close to normoglycemia, i.e. 70-180 mg/dl. On the basis of studies demonstrating an association of TIR with the incidence of diabetes complications, guidelines recommend a target of at least 70% of TIR for most people with diabetes. However, no study has explored the effect of variable degrees of TIR on molecular mechanisms relevant for the development of diabetes complications.<br />Methods: We exposed endothelial cells and monocytes to increasing percentages of TIR, i.e. 50%, 70%, 85% by changing cell media twice a day as appropriate, as well as to constant normoglycemia (i.e. fixed 100 mg/dl of glucose for endothelial cells) and hyperglycemia (i.e. 500 mg/dl glucose), evaluating the development of senescence, of the associated pro-inflammatory response, and monocytes adhesion to endothelial cells as a functional assay. We then assessed the expression of a plethora of markers of senescence and inflammation at the mRNA level in peripheral blood mononuclear cells (PBMC)s derived from individuals with early (i.e. 1-year post-diagnosis) type 1 diabetes (T1D, n = 37), categorized according to the TIR (< or > 70%) observed in the previous 14 days, comparing the two groups through ANCOVA adjusted for HbA1c. As a confirmatory analysis, we also compared the expression of the same markers in people with Time Above Range (TAR), considered as the whole time above 180 mg/dl, ≥ vs < 30%. Correlations between TIR values and the expression of the same markers were tested through linear regression.<br />Results: Constant hyperglycemia promoted the development of senescence in endothelial cells and induced inflammatory responses in both endothelial cells and monocytes, promoting also monocytes adhesion to endothelial cells. A TIR of 70%, but not of 50%, suppressed these effects while a TIR of 85% did not provide additional benefit. Data from people with T1D mirrored such results, as demonstrated by the higher expression of p16, a marker of senescence, and of IL-6, MCP-1, and CXCL1, three inflammatory mediators, in PBMCs from individuals with TIR < 70% and compared with those with TIR > 70%, independently of HbA1c. Similar results were obtained when comparing people with TAR ≥ vs < 30%. When considered as a continuous variable, TIR values were correlated with p16, IL-6, and CXCL1.<br />Conclusions: A TIR above 70% is associated with attenuated pro-senescence and pro-inflammatory effects of hyperglycemia. These molecular results support the TIR target currently recommended by guidelines, especially for people with T1D.<br /> (© 2025. The Author(s).) |
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| ISSN: | 1475-2840 |
| DOI: | 10.1186/s12933-025-02983-3 |