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Apostolopoulou M, Lambadiari V, Roden M, Dimitriadis GD. Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance. Endocr Rev 2025:bnae032. [PMID: 39998445 DOI: 10.1210/endrev/bnae032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Indexed: 02/26/2025]
Abstract
People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.
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Affiliation(s)
- Maria Apostolopoulou
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - George D Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
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Qi L, Geng X, Feng R, Wu S, Fu T, Li N, Ji H, Cheng R, Wu H, Wu D, Huang L, Long Q, Wang X. Association of glycemic variability and prognosis in patients with traumatic brain injury: A retrospective study from the MIMIC-IV database. Diabetes Res Clin Pract 2024; 217:111869. [PMID: 39332533 DOI: 10.1016/j.diabres.2024.111869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 07/28/2024] [Accepted: 09/24/2024] [Indexed: 09/29/2024]
Abstract
BACKGROUND Elevated glycemic variability (GV) often occurs in intensive care unit (ICU) patients and is associated with patient prognosis. However, the association between GV and prognosis in ICU patients with traumatic brain injury (TBI) remains unclear. METHOD Clinical data of ICU patients with TBI were obtained from the Medical Information Mart for Intensive Care (MIMIC) -IV database. The coefficient of variation (CV) was utilized to quantify GV, while the Glasgow Coma Scale (GCS) was employed to evaluate the consciousness status of TBI patients. Pearson linear correlation analysis, linear regression, COX regression and restricted cubic spline (RCS) were used to investigate the relationship between CV and consciousness impairment, as well as the risk of in-hospital mortality. RESULT A total of 1641 ICU patients with TBI were included in the study from the MIMIC-IV database. Pearson linear correlation and restricted cubic spline (RCS) analysis results showed a negative linear relationship between CV and the last GCS (P = 0.002) with no evidence of nonlinearity (P for nonlinear = 0.733). Multivariable linear regression suggested a higher CV was associated with a lower discharge GCS [β (95 %CI) = -1.86 (-3.08 ∼ -0.65), P = 0.003]. Furthermore, multivariable COX regression indicated that CV ≥ 0.3 was a risk factor for in-hospital death in TBI patients [HR (95 %CI) = 1.74 (1.15-2.62), P = 0.003], and this result was also consistent across sensitivity and subgroup analyses. CONCLUSION Higher GV is related to poorer consciousness outcomes and increased risk of in-hospital death in ICU patients with TBI. Additional research is needed to understand the logical relationship between GV and TBI progression.
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Affiliation(s)
- Linrui Qi
- Department of Neurology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Xin Geng
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Rongliang Feng
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Neurosurgery, the First People's Hospital of Zhaoqing City, Zhaoqing 526060, China.
| | - Shuaishuai Wu
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Tengyue Fu
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Ning Li
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Hongming Ji
- Department of Neurosurgery, Shanxi Provincial People's Hospital, Fifth Hospital of Shanxi Medical University, Shanxi Provincial Key Laboratory of Intelligent, Big Data and Digital Neurosurgery, Shanxi Provincial Key Laboratory of Intelligent Brain Tumor, Taiyuan 030012, China.
| | - Rui Cheng
- Department of Neurosurgery, Shanxi Provincial People's Hospital, Fifth Hospital of Shanxi Medical University, Shanxi Provincial Key Laboratory of Intelligent, Big Data and Digital Neurosurgery, Shanxi Provincial Key Laboratory of Intelligent Brain Tumor, Taiyuan 030012, China.
| | - Hao Wu
- Department of Neurosurgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
| | - Dan Wu
- Department of Neurosurgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
| | - Lian Huang
- Department of Neurology, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
| | - Qingshan Long
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Neurosurgery, Zhongshan Torch Development Zone People's Hospital, Zhongshan 528400, China.
| | - Xiangyu Wang
- Department of Neurosurgery, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
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Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, Gao J. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduct Target Ther 2024; 9:234. [PMID: 39289339 PMCID: PMC11408715 DOI: 10.1038/s41392-024-01931-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 06/17/2024] [Accepted: 07/16/2024] [Indexed: 09/19/2024] Open
Abstract
The glucagon-like peptide-1 (GLP-1) receptor, known as GLP-1R, is a vital component of the G protein-coupled receptor (GPCR) family and is found primarily on the surfaces of various cell types within the human body. This receptor specifically interacts with GLP-1, a key hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and several other crucial biological functions. In recent years, GLP-1 medications have become a focal point in the medical community due to their innovative treatment mechanisms, significant therapeutic efficacy, and broad development prospects. This article thoroughly traces the developmental milestones of GLP-1 drugs, from their initial discovery to their clinical application, detailing the evolution of diverse GLP-1 medications along with their distinct pharmacological properties. Additionally, this paper explores the potential applications of GLP-1 receptor agonists (GLP-1RAs) in fields such as neuroprotection, anti-infection measures, the reduction of various types of inflammation, and the enhancement of cardiovascular function. It provides an in-depth assessment of the effectiveness of GLP-1RAs across multiple body systems-including the nervous, cardiovascular, musculoskeletal, and digestive systems. This includes integrating the latest clinical trial data and delving into potential signaling pathways and pharmacological mechanisms. The primary goal of this article is to emphasize the extensive benefits of using GLP-1RAs in treating a broad spectrum of diseases, such as obesity, cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), neurodegenerative diseases, musculoskeletal inflammation, and various forms of cancer. The ongoing development of new indications for GLP-1 drugs offers promising prospects for further expanding therapeutic interventions, showcasing their significant potential in the medical field.
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Affiliation(s)
- Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, WA, 6009, Australia
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yucheng Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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Hu Y, Li Z, Li H, Xu Q, Xu C, Lin W, Ma X, Hao M, Kuang H. Severe hypoglycaemia-induced microglial inflammation damages microvascular endothelial cells, leading to retinal destruction. Diab Vasc Dis Res 2024; 21:14791641241278506. [PMID: 39187253 PMCID: PMC11348349 DOI: 10.1177/14791641241278506] [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] [Indexed: 08/28/2024] Open
Abstract
Human microglia (HMC) are stress-induced inflammatory cells of the retina. It is unknown whether severe hypoglycaemia causes inflammation in microglia, affects the permeability of human retinal microvascular endothelial cells (HRMECs), and causes retinal damage. This study aimed to explore the effects of severe hypoglycaemia on retinal microglial inflammation and endothelial cell permeability and evaluate the damage caused by hypoglycaemia to the retina. The CCK-8 assay was used to measure cell viability. Western blotting was used to detect IL-1β, IL-6, TNF- α, claudin-1, and occludin expression. ELISA was used to detect IL-1β, IL-6, and TNF- α. Transmission electron microscopy (TEM) and haematoxylin and eosin staining were used to observe the retinal structure. Immunohistochemistry and immunofluorescence staining assays were also used to detect IL-1β, IL-6, TNF- α, claudin-1, and occludin expression. Severe hypoglycaemia promoted inflammation in HMC3 cells. Inflammation caused by hypoglycaemia leads to the decreased expression of tight junction proteins. In vivo, severe hypoglycaemia induced structural damage to the retina, increased the expression of inflammatory factors, and decreased the expression of tight junction proteins. Our results suggest that severe hypoglycaemia leads to acute retinal inflammation, affecting the permeability of HRMECs and causing retinal damage.
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Affiliation(s)
- Yuxin Hu
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhen Li
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongxue Li
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Qian Xu
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chengye Xu
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Wenjian Lin
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xuefei Ma
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ming Hao
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Hongyu Kuang
- The Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
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Seaquist E, Giménez M, Yan Y, Matsuhisa M, Kao CY, Wadwa RP, Nagai Y, Khunti K. Nasal Glucagon Reverses Insulin-induced Hypoglycemia With Less Rebound Hyperglycemia: Pooled Analysis of Clinical Trials. J Endocr Soc 2024; 8:bvae034. [PMID: 38444629 PMCID: PMC10913376 DOI: 10.1210/jendso/bvae034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Indexed: 03/07/2024] Open
Abstract
Background Rebound hyperglycemia may occur following glucagon treatment for severe hypoglycemia. We assessed rebound hyperglycemia occurrence after nasal glucagon (NG) or injectable glucagon (IG) administration in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). Methods This was a pooled analysis of 3 multicenter, randomized, open-label studies (NCT03339453, NCT03421379, NCT01994746) in patients ≥18 years with T1D or T2D with induced hypoglycemia. Proportions of patients achieving treatment success [blood glucose (BG) increase to ≥70 mg/dL or increase of ≥20 mg/dL from nadir within 15 and 30 minutes]; BG ≥70 mg/dL within 15 minutes; in-range BG (70-180 mg/dL) 1 to 2 and 1 to 4 hours postdose; and BG >180 mg/dL 1 to 2 and 1 to 4 hours postdose were compared. Incremental area under curve (iAUC) of BG >180 mg/dL and area under curve (AUC) of observed BG values postdose were analyzed. Safety was assessed in all studies. Results Higher proportions of patients had in-range BG with NG vs IG (1-2 hours: P = .0047; 1-4 hours: P = .0034). Lower proportions of patients had at least 1 BG value >180 mg/dL with NG vs IG (1-2 hours: P = .0034; 1-4 hours: P = .0068). iAUC and AUC were lower with NG vs IG (P = .025 and P < .0001). As expected, similar proportions of patients receiving NG or IG achieved treatment success at 15 and 30 minutes (97-100%). Most patients had BG ≥70 mg/dL within 15 minutes (93-96%). The safety profile was consistent with previous studies. Conclusion This study demonstrated lower rebound hyperglycemia risk after NG treatment compared with IG. Clinical Trial Registration NCT03421379, NCT03339453, NCT01994746.
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Affiliation(s)
- Elizabeth Seaquist
- Department of Medicine, Division of Endocrinology and Diabetes, University of Minnesota, Minneapolis, MN 55455, USA
| | - Marga Giménez
- Diabetes Unit, Endocrinology and Nutrition Department, Hospital Clínic de Barcelona, Barcelona 08036, Spain
| | - Yu Yan
- Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima 770-8503, Japan
| | | | - R Paul Wadwa
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Yukiko Nagai
- Eli Lilly and Company, Indianapolis, IN 46225, USA
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester LE1 7RH, UK
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Mo Y, Lu J, Zhou J. Glycemic variability: Measurement, target, impact on complications of diabetes and does it really matter? J Diabetes Investig 2024; 15:5-14. [PMID: 37988220 PMCID: PMC10759720 DOI: 10.1111/jdi.14112] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 11/05/2023] [Accepted: 11/08/2023] [Indexed: 11/23/2023] Open
Abstract
Over the past two decades, there has been continuous advancement in the accuracy and complexity of continuous glucose monitoring devices. Continuous glucose monitoring provides valuable insights into blood glucose dynamics, and can record glucose fluctuations accurately and completely. Glycemic variability (GV) is a straightforward measure of the extent to which a patient's blood glucose levels fluctuate between high peaks and low nadirs. Many studies have investigated the relationship between GV and complications, primarily in the context of type 2 diabetes. Nevertheless, the exact contribution of GV to the development of diabetes complications remains unclear. In this literature review, we aimed to summarize the existing evidence regarding the measurement, target level, pathophysiological mechanisms relating GV and tissue damage, and population-based studies of GV and diabetes complications. Additionally, we introduce novel methods for measuring GV, and discuss several unresolved issues of GV. In the future, more longitudinal studies and trials are required to confirm the exact role of GV in the development of diabetes complications.
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Affiliation(s)
- Yifei Mo
- Department of Endocrinology and MetabolismShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes MellitusShanghaiChina
| | - Jingyi Lu
- Department of Endocrinology and MetabolismShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes MellitusShanghaiChina
| | - Jian Zhou
- Department of Endocrinology and MetabolismShanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes MellitusShanghaiChina
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Ünlütürk U, Bahçecioğlu AB, Samadi A, Lay I, Bayraktar M, Dağdelen S. Glycemic variability leads to higher levels of auto-oxidized oxysterol species in patients with type 1 diabetes mellitus. J Endocrinol Invest 2023; 46:2547-2554. [PMID: 37188911 DOI: 10.1007/s40618-023-02110-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 05/08/2023] [Indexed: 05/17/2023]
Abstract
PURPOSE Hyperglycemia and glycemic variability (GV) are associated with oxidative stress in patients with diabetes mellitus (DM). Oxysterol species, produced by the non-enzymatic oxidation of cholesterol, are potential biomarkers of oxidative stress. This study examined the relationship between auto-oxidized oxysterols and GV in patients with type 1 DM. METHODS Thirty patients with type 1 DM using a continuous subcutaneous insulin infusion pump therapy and a healthy control group (n = 30) were included in this prospective study. A Continuous Glucose Monitoring System device was applied for 72 h. Blood samples were taken for oxysterols produced by non-enzymatic oxidation [7-ketocholesterol (7-KC) and cholestane-3β, 5α, 6β-triol (Chol-Triol)] levels at 72 h. Short-term glycemic variability parameters, mean amplitude of glycemic excursions (MAGE), the standard deviation of glucose measurements (Glucose-SD), and mean of daily differences (MODD) were calculated with continuous glucose monitoring data. HbA1c was used to evaluate glycemic control and HbA1c-SD (the SD of HbA1c over the past year) for long-term glycemic variability. RESULTS 7-KC and Chol-triol levels were significantly higher in the study group than in the control group. Strong positive correlations were found between 7-KC with MAGE(24-48 h) and Glucose-SD(24-48 h). 7-KC was positively correlated with MAGE(0-72 h) and Glucose-SD(0-72 h). No significant correlation was found between HbA1c and HbA1c -SD with oxysterol levels. The regression models showed that SD(24-48 h) and MAGE(24-48 h) predicted 7-KC levels while HbA1c did not. CONCLUSIONS Glycemic variability leads to higher levels of auto-oxidized oxysterol species in patients with type 1 DM independent of long-term glycemic control.
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Affiliation(s)
- U Ünlütürk
- Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey.
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey.
| | - A B Bahçecioğlu
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
| | - A Samadi
- Department of Medical Biochemistry, School of Medicine, Hacettepe University, Ankara, Turkey
- Joint Laboratory of Applied Ecotoxicology, Korea Institute of Science and Technology Europe, KIST EU), Campus 7.1, 66123, Saarbrucken, Germany
| | - I Lay
- Department of Medical Biochemistry, School of Medicine, Hacettepe University, Ankara, Turkey
| | - M Bayraktar
- Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
| | - S Dağdelen
- Division of Endocrinology and Metabolism, Hacettepe University School of Medicine, Ankara, Turkey
- Department of Internal Medicine, Hacettepe University, Ankara, Turkey
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Harvengt AA, Polle OG, Martin M, van Maanen A, Gatto L, Lysy PA. Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes. PLoS One 2023; 18:e0294982. [PMID: 38033011 PMCID: PMC10688654 DOI: 10.1371/journal.pone.0294982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 11/14/2023] [Indexed: 12/02/2023] Open
Abstract
AIMS To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. METHODS In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual β-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. RESULTS PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual β-cell secretion (R2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. CONCLUSION PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.
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Affiliation(s)
- Antoine A. Harvengt
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Olivier G. Polle
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Manon Martin
- Computational Biology and Bioinformatics (CBIO) Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Aline van Maanen
- Statistical Support Unit, Institut Roi Albert II, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Laurent Gatto
- Computational Biology and Bioinformatics (CBIO) Unit, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Philippe A. Lysy
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
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Chambers ME, Nuibe EH, Reno-Bernstein CM. Brain Regulation of Cardiac Function during Hypoglycemia. Metabolites 2023; 13:1089. [PMID: 37887414 PMCID: PMC10608630 DOI: 10.3390/metabo13101089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/02/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023] Open
Abstract
Hypoglycemia occurs frequently in people with type 1 and type 2 diabetes. Hypoglycemia activates the counter-regulatory response. Besides peripheral glucose sensors located in the pancreas, mouth, gastrointestinal tract, portal vein, and carotid body, many brain regions also contain glucose-sensing neurons that detect this fall in glucose. The autonomic nervous system innervates the heart, and during hypoglycemia, can cause many changes. Clinical and animal studies have revealed changes in electrocardiograms during hypoglycemia. Cardiac repolarization defects (QTc prolongation) occur during moderate levels of hypoglycemia. When hypoglycemia is severe, it can be fatal. Cardiac arrhythmias are thought to be the major mediator of sudden death due to severe hypoglycemia. Both the sympathetic and parasympathetic nervous systems of the brain have been implicated in regulating these arrhythmias. Besides cardiac arrhythmias, hypoglycemia can have profound changes in the heart and most of these changes are exacerbated in the setting of diabetes. A better understanding of how the brain regulates cardiac changes during hypoglycemia will allow for better therapeutic intervention to prevent cardiovascular death associated with hypoglycemia in people with diabetes. The aim of this paper is to provide a narrative review of what is known in the field regarding how the brain regulates the heart during hypoglycemia.
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Affiliation(s)
| | | | - Candace M. Reno-Bernstein
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112, USA (E.H.N.)
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Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
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Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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11
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McNeilly AD, Gallagher JR, Evans ML, de Galan BE, Pedersen-Bjergaard U, Thorens B, Dinkova-Kostova AT, Huang JT, Ashford MLJ, McCrimmon RJ. Chronic hyperglycaemia increases the vulnerability of the hippocampus to oxidative damage induced during post-hypoglycaemic hyperglycaemia in a mouse model of chemically induced type 1 diabetes. Diabetologia 2023; 66:1340-1352. [PMID: 37015997 PMCID: PMC10244284 DOI: 10.1007/s00125-023-05907-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/26/2023] [Indexed: 04/06/2023]
Abstract
AIMS/HYPOTHESIS Chronic hyperglycaemia and recurrent hypoglycaemia are independently associated with accelerated cognitive decline in type 1 diabetes. Recurrent hypoglycaemia in rodent models of chemically induced (streptozotocin [STZ]) diabetes leads to cognitive impairment in memory-related tasks associated with hippocampal oxidative damage. This study examined the hypothesis that post-hypoglycaemic hyperglycaemia in STZ-diabetes exacerbates hippocampal oxidative stress and explored potential contributory mechanisms. METHODS The hyperinsulinaemic glucose clamp technique was used to induce equivalent hypoglycaemia and to control post-hypoglycaemic glucose levels in mice with and without STZ-diabetes and Nrf2-/- mice (lacking Nrf2 [also known as Nfe2l2]). Subsequently, quantitative proteomics based on stable isotope labelling by amino acids in cell culture and biochemical approaches were used to assess oxidative damage and explore contributory pathways. RESULTS Evidence of hippocampal oxidative damage was most marked in mice with STZ-diabetes exposed to post-hypoglycaemic hyperglycaemia; these mice also showed induction of Nrf2 and the Nrf2 transcriptional targets Sod2 and Hmox-1. In this group, hypoglycaemia induced a significant upregulation of proteins involved in alternative fuel provision, reductive biosynthesis and degradation of damaged proteins, and a significant downregulation of proteins mediating the stress response. Key differences emerged between mice with and without STZ-diabetes following recovery from hypoglycaemia in proteins mediating the stress response and reductive biosynthesis. CONCLUSIONS/INTERPRETATION There is a disruption of the cellular response to a hypoglycaemic challenge in mice with STZ-induced diabetes that is not seen in wild-type non-diabetic animals. The chronic hyperglycaemia of diabetes and post-hypoglycaemic hyperglycaemia act synergistically to induce oxidative stress and damage in the hippocampus, possibly leading to irreversible damage/modification to proteins or synapses between cells. In conclusion, recurrent hypoglycaemia in sub-optimally controlled diabetes may contribute, at least in part, to accelerated cognitive decline through amplifying oxidative damage in key brain regions, such as the hippocampus. DATA AVAILABILITY The datasets generated during and/or analysed during the current study are available in ProteomeXchange, accession no. 1-20220824-173727 ( www.proteomexchange.org ). Additional datasets generated during and/or analysed during the present study are available from the corresponding author upon reasonable request.
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Affiliation(s)
- Alison D McNeilly
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Jennifer R Gallagher
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Mark L Evans
- Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Bastiaan E de Galan
- Radboud University Medical Center, Nijmegen, the Netherlands
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, the Netherlands
| | | | - Bernard Thorens
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
| | - Albena T Dinkova-Kostova
- Division of Cancer Research, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Jeffrey-T Huang
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
- Biomarker and Drug Analysis Core Facility, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Michael L J Ashford
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK
| | - Rory J McCrimmon
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, Dundee, UK.
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12
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Christou MA, Christou PA, Kyriakopoulos C, Christou GA, Tigas S. Effects of Hypoglycemia on Cardiovascular Function in Patients with Diabetes. Int J Mol Sci 2023; 24:9357. [PMID: 37298308 PMCID: PMC10253702 DOI: 10.3390/ijms24119357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 05/21/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Hypoglycemia is common in patients with type 1 and type 2 diabetes (T1D, T2D), treated with insulin or sulfonylureas, and has multiple short- and long-term clinical implications. Whether acute or recurrent, hypoglycemia significantly affects the cardiovascular system with the potential to cause cardiovascular dysfunction. Several pathophysiological mechanisms have been proposed linking hypoglycemia to increased cardiovascular risk, including hemodynamic changes, myocardial ischemia, abnormal cardiac repolarization, cardiac arrhythmias, prothrombotic and proinflammatory effects, and induction of oxidative stress. Hypoglycemia-induced changes can promote the development of endothelial dysfunction, which is an early marker of atherosclerosis. Although data from clinical trials and real-world studies suggest an association between hypoglycemia and cardiovascular events in patients with diabetes, it remains uncertain whether this association is causal. New therapeutic agents for patients with T2D do not cause hypoglycemia and have cardioprotective benefits, whereas increasing the use of new technologies, such as continuous glucose monitoring devices and insulin pumps, has the potential to reduce hypoglycemia and its adverse cardiovascular outcomes in patients with T1D.
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Affiliation(s)
- Maria A. Christou
- Department of Endocrinology, University of Ioannina Faculty of Medicine, 45500 Ioannina, Greece; (M.A.C.); (P.A.C.)
| | - Panagiota A. Christou
- Department of Endocrinology, University of Ioannina Faculty of Medicine, 45500 Ioannina, Greece; (M.A.C.); (P.A.C.)
| | - Christos Kyriakopoulos
- Department of Respiratory Medicine, University of Ioannina Faculty of Medicine, 45500 Ioannina, Greece;
| | - Georgios A. Christou
- Laboratory of Physiology, University of Ioannina Faculty of Medicine, 45500 Ioannina, Greece;
| | - Stelios Tigas
- Department of Endocrinology, University of Ioannina Faculty of Medicine, 45500 Ioannina, Greece; (M.A.C.); (P.A.C.)
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13
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Tynjälä A, Harjutsalo V, Jansson Sigfrids F, Groop PH, Gordin D. Higher HbA 1c variability is associated with increased arterial stiffness in individuals with type 1 diabetes. Cardiovasc Diabetol 2023; 22:47. [PMID: 36871019 PMCID: PMC9985852 DOI: 10.1186/s12933-023-01770-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/13/2023] [Indexed: 03/06/2023] Open
Abstract
BACKGROUND Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes. METHODS This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA1c from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA1c variability was calculated as adjusted standard deviation (adj-HbA1c-SD), coefficient of variation (HbA1c-CV) and average real variability (HbA1c-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry. RESULTS The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA1c assessments per individual was 17 (12-26). All three indices of HbA1c variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA1c-SD and HbA1c-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA1c-mean. HbA1c-ARV was not associated with cfPWV or AIx in the fully adjusted models. CONCLUSIONS An association independent of HbA1c-mean was found between HbA1c variability and arterial stiffness, suggesting a need to consider multiple HbA1c metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability.
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Affiliation(s)
- Anniina Tynjälä
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Fanny Jansson Sigfrids
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.,Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland. .,Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. .,Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. .,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia.
| | - Daniel Gordin
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
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14
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Liu AS, Fan ZH, Lu XJ, Wu YX, Zhao WQ, Lou XL, Hu JH, Peng XYH. The characteristics of postprandial glycemic response patterns to white rice and glucose in healthy adults: Identifying subgroups by clustering analysis. Front Nutr 2022; 9:977278. [PMID: 36386904 PMCID: PMC9659901 DOI: 10.3389/fnut.2022.977278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/03/2022] [Indexed: 04/10/2024] Open
Abstract
OBJECTIVES Large interpersonal variability in postprandial glycemic response (PGR) to white rice has been reported, and differences in the PGR patterns during the oral glucose tolerance test (OGTT) have been documented. However, there is scant study on the PGR patterns of white rice. We examined the typical PGR patterns of white rice and glucose and the association between them. MATERIALS AND METHODS We analyzed the data of 3-h PGRs to white rice (WR) and glucose (G) of 114 normoglycemic female subjects of similar age, weight status, and same ethnic group. Diverse glycemic parameters, based on the discrete blood glucose values, were calculated over 120 and 180 min. K-means clustering based on glycemic parameters calculated over 180 min was applied to identify subgroups and representative PGR patterns. Principal factor analysis based on the parameters used in the cluster analysis was applied to characterize PGR patterns. Simple correspondence analysis was performed on the clustering categories of WR and G. RESULTS More distinct differences were found in glycemic parameters calculated over 180 min compared with that calculated over 120 min, especially in the negative area under the curve and Nadir. We identified four distinct PGR patterns to WR (WR1, WR2, WR3, and WR4) and G (G1, G2, G3, and G4), respectively. There were significant differences among the patterns regard to postprandial hyperglycemia, hypoglycemic, and glycemic variability. The WR1 clusters had significantly lower glycemic index (59 ± 19), while no difference was found among the glycemic index based on the other three clusters. Each given G subgroup presented multiple patterns of PGR to WR, especially in the largest G subgroup (G1), and in subgroup with the greatest glycemic variability (G3). CONCLUSION Multiple subgroups could be classified based on the PGR patterns to white rice and glucose even in seemingly homogeneous subjects. Extending the monitoring time to 180 min was conducive to more effective discrimination of PGR patterns. It may not be reliable to extrapolate the patterns of PGR to rice from that to glucose, suggesting a need of combining OGTT and meal tolerance test for individualized glycemic management.
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Affiliation(s)
- An-shu Liu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Zhi-hong Fan
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, China
| | - Xue-jiao Lu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Yi-xue Wu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Wen-qi Zhao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xin-ling Lou
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Jia-hui Hu
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Xi-yi-he Peng
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
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15
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Gauer JS, Ajjan RA, Ariëns RAS. Platelet-Neutrophil Interaction and Thromboinflammation in Diabetes: Considerations for Novel Therapeutic Approaches. J Am Heart Assoc 2022; 11:e027071. [PMID: 36250653 DOI: 10.1161/jaha.122.027071] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Thromboinflammation has become a topic of key interest in cardiovascular disease and the prevention of diabetes complications because of the interplay between thrombosis and inflammation in diabetes. Specifically, the significant risk of vascular thrombotic disease in diabetes highlights the need for new and better therapeutic targets to help manage and prevent vascular thrombo-occlusive disease in this condition. Similarly, the prominent role of inflammation in diabetes has sparked interest in anti-inflammatory agents to better prevent and control vascular disease. Investigations on the effects of anticoagulation and antiplatelet interventions in patients with diabetes and cardiovascular disease show a potential role for these agents in decreasing morbidity and mortality. Neutrophils and platelets are key players in inflammation and wound-healing response, respectively. The interaction between neutrophils and platelets is thought to be an important driver of thromboinflammation. Therefore, this review describes the mechanisms involved in platelet-neutrophil interactions that contribute to the development or exacerbation of thromboinflammation in the context of diabetes and its associated comorbidities. The effects observed by the antithrombotic/antidiabetic treatments and physical activity/dietary interventions on attenuating thromboinflammation are discussed. These data suggest that mechanisms involved in platelet-neutrophil interaction, platelet activation/aggregation, and the recruitment of neutrophils have a promising potential to become therapeutic targets to decrease thromboinflammation in patients with diabetes.
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Affiliation(s)
- Julia S Gauer
- Discovery and Translational Science Department Institute of Cardiovascular and Metabolic Medicine, University of Leeds Leeds United Kingdom
| | - Ramzi A Ajjan
- Discovery and Translational Science Department Institute of Cardiovascular and Metabolic Medicine, University of Leeds Leeds United Kingdom
| | - Robert A S Ariëns
- Discovery and Translational Science Department Institute of Cardiovascular and Metabolic Medicine, University of Leeds Leeds United Kingdom
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16
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Kethireddy R, Gandhi D, Kichloo A, Patel L. Challenges in hyperglycemia management in critically ill patients with COVID-19. World J Crit Care Med 2022; 11:219-227. [PMID: 36051939 PMCID: PMC9305683 DOI: 10.5492/wjccm.v11.i4.219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 08/10/2021] [Accepted: 05/08/2022] [Indexed: 02/06/2023] Open
Abstract
Hyperglycemia is commonly associated with adverse outcomes especially in patients requiring intensive care unit stay. Data from the corona virus disease 2019 (COVID-19) pandemic indicates that individuals with diabetes appear to be at similar risk for COVID-19 infection to those without diabetes but are more likely to experience increased morbidity and mortality. The proposed hypothesis for hyperglycemia in COVID-19 include insulin resistance, critical illness hyperglycemia (stress- induced hyperglycemia) secondary to high levels of hormones like cortisol and catecholamines that counteract insulin action, acute cytokine storm and pancreatic cell dysfunction. Diabetic patients are more likely to have severe hyperglycemic complications including diabetic ketoacidosis and hyperosmolar hyperglycemic state. Management of hyperglycemia in COVID-19 is often complicated by use of steroids, prolonged total parenteral or enteral nutrition, frequent acute hyperglycemic events, and restrictions with fluid management due to acute respiratory distress syndrome. While managing hyperglycemia special attention should be paid to mode of insulin delivery, frequency of glucose monitoring based on patient and caregiver safety thereby minimizing exposure and conserving personal protective equipment. In this article we describe the pathophysiology of hyperglycemia, challenges encountered in managing hyperglycemia, and review some potential solutions to address them.
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Affiliation(s)
- Rajesh Kethireddy
- Division of Hospital Medicine, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
| | - Darshan Gandhi
- Department of Diagnostic Radiology, University of Tennessee Health Science Center, Memphis, TN 38103, United States
| | - Asim Kichloo
- Internal Medicine, Central Michigan University School of Medicine, Mt Pleasant, MI 48859, United States
| | - Love Patel
- Division of Hospital Medicine, Abbott Northwestern Hospital, Allina Health, Minneapolis, MN 55407, United States
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17
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Vrebalov Cindro P, Krnić M, Modun D, Vuković J, Tičinović Kurir T, Kardum G, Rušić D, Šešelja Perišin A, Bukić J. Comparison of the Impact of Insulin Degludec U100 and Insulin Glargine U300 on Glycemic Variability and Oxidative Stress in Insulin-Naive Patients With Type 2 Diabetes Mellitus: Pilot Study for a Randomized Trial. JMIR Form Res 2022; 6:e35655. [PMID: 35802405 PMCID: PMC9308081 DOI: 10.2196/35655] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 05/30/2022] [Accepted: 06/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background
There is an ongoing discussion about possible differences between insulin degludec (IDeg-100) and glargine U300 (IGlar-300). There is little data and head-to-head comparison of IDeg-100 and IGlar-300 regarding their simultaneous impact on glycemic variability and oxidative stress in patients with type 2 diabetes mellitus (T2DM).
Objective
In our randomized, open-label, crossover study, we compared the impact of IDeg-100 and IGlar-300 on glycemic variability and oxidative stress in insulin-naive patients with T2DM.
Methods
We recruited a total of 25 adult patients with T2DM (7 females) whose diabetes was uncontrolled (HbA1c ≥7.5%) on two or more oral glucose-lowering drugs; a total of 22 completed the study. Mean age was 57.3 (SD 6.99) years and duration of diabetes was 9.94 (SD 5.01) years. After the washout period, they were randomized alternately to first receive either IDeg-100 or IGlar-300 along with metformin. Each insulin was administered for 12 weeks and then switched. At the beginning and end of each phase, biochemical and oxidative stress parameters were analyzed. On 3 consecutive days prior to each control point, patients performed a 7-point self-monitoring of blood glucose profile. Oxidative stress was assessed by measuring thiol groups and hydroperoxides (determination of reactive oxygen metabolites test) in serum.
Results
IGlar-300 reduced mean glucose by 0.02-0.13 mmol/L, and IDeg-100 reduced glucose by 0.10-0.16 mmol/L, with no significant difference. The reduction of the coefficient of glucose variation also did not show a statistically significant difference. IGlar-300 increased thiols by 0.08 µmol/L and IDeg-100 increased thiols by 0.15 µmol/L, with no significant difference (P=.07) between them. IGlar-300 reduced hydroperoxides by 0.040 CARR U and IDeg-100 increased hydroperoxides by 0.034 CARR U, but the difference was not significant (P=.12).
Conclusions
The results of our study do not show a significant difference regarding glycemic variability between patients receiving either insulin IDeg-100 or IGlar-300, although IGlar-300 showed greater dispersion of data. No significant difference in oxidative stress was observed. In a larger study, doses of insulins should be higher to achieve significant impact on glycemic parameters and consequently on glycemic variability and oxidative stress.
Trial Registration
ClinicalTrials.gov, NCT04692415; https://clinicaltrials.gov/ct2/show/NCT04692415
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Affiliation(s)
| | - Mladen Krnić
- Department of Endocrinology, University Hospital Split, Split, Croatia
- Department of Pathophysiology, School of Medicine, University of Split, Split, Croatia
| | - Darko Modun
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Jonatan Vuković
- Department of Gastroenterology, University Hospital Split, Split, Croatia
| | - Tina Tičinović Kurir
- Department of Endocrinology, University Hospital Split, Split, Croatia
- Department of Pathophysiology, School of Medicine, University of Split, Split, Croatia
| | - Goran Kardum
- Department of Psychology, Faculty of Humanities and Social Sciences, University of Split, Split, Croatia
| | - Doris Rušić
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Ana Šešelja Perišin
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
| | - Josipa Bukić
- Department of Pharmacy, School of Medicine, University of Split, Split, Croatia
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18
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Batule S, Ramos A, Pérez-Montes de Oca A, Fuentes N, Martínez S, Raga J, Pena X, Tural C, Muñoz P, Soldevila B, Alonso N, Umpierrez G, Puig-Domingo M. Comparison of Glycemic Variability and Hypoglycemic Events in Hospitalized Older Adults Treated with Basal Insulin plus Vildagliptin and Basal-Bolus Insulin Regimen: A Prospective Randomized Study. J Clin Med 2022; 11:jcm11102813. [PMID: 35628938 PMCID: PMC9143484 DOI: 10.3390/jcm11102813] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/10/2022] [Accepted: 05/12/2022] [Indexed: 12/10/2022] Open
Abstract
Background: The basal−bolus insulin regimen is recommended in hospitalized patients with diabetes mellitus (DM), but has an increased risk of hypoglycemia. We aimed to compare dipeptidyl peptidase 4 inhibitors (DPP4-i) and basal−bolus insulin glycemic outcomes in hospitalized type 2 DM patients. Methods and patients: Our prospective randomized study included 102 elderly T2DM patients (82 ± 9 years, HbA1c 6.6% ± 1.9). Glycemic control: A variability coefficient assessed by continuous glucose monitoring (Free Style® sensor), mean insulin dose and hypoglycemia rates obtained with the two treatments were analyzed. Results: No differences were found between groups in glycemic control (mean daily glycemia during the first 10 days: 152.6 ± 38.5 vs. 154.2 ± 26.3 mg/dL; p = 0.8). The total doses Kg/day were 0.40 vs. 0.20, respectively (p < 0.001). A lower number of hypoglycemic events (9% vs. 15%; p < 0.04) and lower glycemic coefficient of variation (22% vs. 28%; p < 0.0002) were observed in the basal−DPP4-i compared to the basal−bolus regimen group. Conclusions: Treatment of inpatient hyperglycemia with basal insulin plus DPP4-i is an effective and safe regimen in old subjects with T2DM, with a similar mean daily glucose concentration, but lower glycemic variability and fewer hypoglycemic episodes compared to the basal bolus insulin regimen.
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Affiliation(s)
- Sol Batule
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Analía Ramos
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Alejandra Pérez-Montes de Oca
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Natalia Fuentes
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Santiago Martínez
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Joan Raga
- Servicio de Medicina Interna, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (J.R.); (X.P.); (C.T.); (P.M.)
| | - Xoel Pena
- Servicio de Medicina Interna, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (J.R.); (X.P.); (C.T.); (P.M.)
| | - Cristina Tural
- Servicio de Medicina Interna, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (J.R.); (X.P.); (C.T.); (P.M.)
| | - Pilar Muñoz
- Servicio de Medicina Interna, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (J.R.); (X.P.); (C.T.); (P.M.)
| | - Berta Soldevila
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | - Nuria Alonso
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
| | | | - Manel Puig-Domingo
- Servicio de Endocrinología y Nutrición, Hospital Germans Trias i Pujol, 08916 Badalona, Spain; (S.B.); (A.R.); (A.P.-M.d.O.); (N.F.); (S.M.); (B.S.); (N.A.)
- Correspondence: ; Tel.: +34-93-497-88-60
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Lee YE, Lee EJ, Lee SE, Park J. Predictors of consciousness improvement in patients with hypoglycemic encephalopathy. Front Endocrinol (Lausanne) 2022; 13:956367. [PMID: 36051391 PMCID: PMC9424633 DOI: 10.3389/fendo.2022.956367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022] Open
Abstract
AIMS Hypoglycemic encephalopathy (HE) can cause long-lasting mental changes, disability, and even death. We aimed to investigate prognostic factors for HE and to determine when the treatment of HE becomes futile. METHODS We retrospectively evaluated the data of patients admitted for prolonged HE at Dongguk University Ilsan Hospital between December 2005 and July 2021. We assessed the Glasgow Outcome Scale (GOS) to assess functional outcome. RESULTS Forty-four patients were enrolled in the study. Thirty-two of these showed the improvement on GOS after treatment. Patients with improved consciousness had a shorter duration of hypoglycemia (1.6±1.4 vs. 7.8±15.0 hours, p = 0.04) and a lower incidence of brain lesions than those without improvements in consciousness (76.0% vs. 25.0%, p < 0.01). Patients whose lesions were detected in initial MRIs were 1.3 times less likely to recover consciousness after HE (odds ratios, 1.28; 95% CI, 1.09-1.52; p < 0.01). None of the patients recovered consciousness after 320 h. Maximum time spent to recover was 194 in patients without brain lesions and 319 in those with lesions. CONCLUSIONS Hypoglycemic brain injury detected in initial MRIs predicted poorer HE prognosis. Nevertheless, treatment should be provided for at least for 14 days after admission.
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Affiliation(s)
- Yu Eun Lee
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, South Korea
| | - Eun Ja Lee
- Department of Radiology, Dongguk University Ilsan Hospital, Goyang, South Korea
| | - Seung Eun Lee
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, South Korea
- *Correspondence: Jinkyeong Park, ; Seung Eun Lee,
| | - Jinkyeong Park
- Department of Pulmonary, Allergy and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul, South Korea
- *Correspondence: Jinkyeong Park, ; Seung Eun Lee,
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20
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Colinet V, Lysy PA. Characterization of Post-Hypoglycemic Hyperglycemia in Children and Adolescents With Type 1 Diabetes: The EPHICA Study. Front Endocrinol (Lausanne) 2022; 13:887976. [PMID: 35832426 PMCID: PMC9272988 DOI: 10.3389/fendo.2022.887976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/17/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND In patients with diabetes, the dynamics in which hypoglycemia recovers impacts cardiovascular disease risk. Our study investigated the extents of "post-hypoglycemic hyperglycemia (PHH)" (i.e. hypoglycemia that recover to hyperglycemia in any circumstance) and factors likely to influence PHH characteristics in a pediatric cohort of patients with type 1 diabetes (T1D). METHODS We collected retrospective continuous glucose monitoring (CGM) data from 142 pediatric patients with T1D to characterize episodes of PHH during a two-month follow-up period. Factors influencing PHH were determined using univariate and multivariate analyses. RESULTS In our EPHICA cohort, PHH rate was 0.6 ± 0.3 episode/day and correlated (r=0.33; p<0.0001) with hyperglycemia rate (2.6 ± 0.5 episodes/day). The global proportion of hyperglycemia corresponding to PHH was 0.22 ± 0.1, yet 14.8% of patients had more than 1/3 of hyperglycemia related to PHH. Episodes of PHH lasted 239.6 ± 124.8 minutes with a hyperglycemic peak of 258.8 ± 47.1 mg/dL. Only 12.2% of PHH occurred at night. While a younger age (<12 years) and lower body mass index (BMI) (SDS: -2 to 1.6) were associated with higher daily PHH rates, teenagers (≥12 years) and obese patients experienced longer PHH and higher hyperglycemic peaks. Parameters of glycemic variability (i.e. HbA1C, IDAA1C and GTAA1C) moderately correlated with PHH duration and related hyperglycemic peak. Multivariate analysis confirmed these results, as factors likely to influence PHH rate were phenotype (age and BMI) and glycemic variability parameters (time in range, mean glycemia, HbA1C and GTAA1C). CONCLUSION Our EPHICA study highlights the importance of PHH as a prominent component of hyperglycemia in some children and adolescents with T1D. Factors associated with PHH features are age, BMI and parameters of glycemic control. Young and lean children are more prone to experience hypoglycemia that recover with hyperglycemia, but adolescents and obese children tend to experience hyperglycemia of longer duration.
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Affiliation(s)
- Victoria Colinet
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Philippe A. Lysy
- Pôle PEDI, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
- Specialized Pediatrics Service, Cliniques universitaires Saint-Luc, Brussels, Belgium
- *Correspondence: Philippe A. Lysy,
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21
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Ceriello A, Prattichizzo F, Phillip M, Hirsch IB, Mathieu C, Battelino T. Glycaemic management in diabetes: old and new approaches. Lancet Diabetes Endocrinol 2022; 10:75-84. [PMID: 34793722 DOI: 10.1016/s2213-8587(21)00245-x] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/13/2021] [Accepted: 08/20/2021] [Indexed: 12/12/2022]
Abstract
HbA1c is the most used parameter to assess glycaemic control. However, evidence suggests that the concept of hyperglycaemia has profoundly changed and that different facets of hyperglycaemia must be considered. A modern approach to glycaemic control should focus not only on reaching and maintaining optimal HbA1c concentrations as early as possible, but to also do so by reducing postprandial hyperglycaemia, glycaemic variability, and to extend as much as possible the time in range in near-normoglycaemia. These goals should be achieved while avoiding hypoglycaemia, which, should it occur, should be reverted to normoglycaemia. Modern technology, such as intermittently scanned glucose monitoring and continuous glucose monitoring, together with new drug therapies (eg, ultra-fast insulins, SGLT2 inhibitors, and GLP-1 receptor agonists), could help to change the landscape of glycaemia management based on HbA1c in favour of a more holistic approach that considers all the different aspects of this commonly oversimplified pathophysiological feature of diabetes.
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Affiliation(s)
| | | | - Moshe Phillip
- Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Irl B Hirsch
- University of Washington School of Medicine, Seattle, WA, USA
| | - Chantal Mathieu
- Department of Endocrinology, UZ Gasthuisberg KU Leuven, Leuven, Belgium
| | - Tadej Battelino
- University Medical Center Ljubljana, University Children's Hospital, Ljubljana, Slovenia; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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22
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Cunha FM, Cidade-Rodrigues C, Elias C, Oliveira D, Bettencourt P, Lourenço P. Glucose variability predicts 6-month mortality in patients hospitalized with acute heart failure. Intern Emerg Med 2021; 16:2121-2128. [PMID: 33818704 DOI: 10.1007/s11739-021-02719-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 03/17/2021] [Indexed: 12/29/2022]
Abstract
In diabetes mellitus (DM), glycaemic fluctuations associate with higher oxidative stress than sustained chronic hyperglycaemia and glucose variability increases the risk of chronic diabetic complications. Our hypothesis was that higher glucose variability would associate with mortality after an acute heart failure (HF) episode. We retrospectively analysed patients with DM hospitalized with acute HF between 2009 and 2010. Patients with < 2 point-of-care glucose values/day were excluded. Glucose coefficient of variation (GCV) was defined as (glucose standard deviation/mean glucose) × 100. Patients were categorized according GCV ≤ 30.0 and > 30.0%. Follow-up: 6-months. Endpoint: all-cause mortality. A Cox-regression analysis was used to study the association of glucose variability with 6-month mortality. We studied 214 diabetic patients with acute HF, 49.1% male, mean age 76 years. Mean glycaemia during hospitalization was 187 ± 50 mg/dL, hypoglycaemia (< 70 mg/dL) was reported in 21 patients and mean GCV was 28.3 ± 7.6%. Patients with GCV > 30.0% had higher mean glycaemia, more hypoglycaemic episodes and higher HbA1c; they were also more often treated with insulin. Patients were similar concerning age, gender, comorbidities, left ventricular systolic dysfunction and ischemic heart disease. During the 6-month follow-up, 38 (17.8%) patients died. Patients with GCV > 30.0% had a HR of 6-month mortality of 2.21 (95% CI: 1.16-4.21), p = 0.02. This association with more than twofold higher short-term mortality was independent of main confounders. Elevated glycaemic variability in acute HF admissions of patients with DM predicts short-term mortality. Patients with GCV > 30.0% have an independent more than twofold higher risk of 6-month death after an acute HF hospitalization.
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Affiliation(s)
- Filipe M Cunha
- Endocrinology Department, Centro Hospitalar do Tâmega e Sousa, Avenida Do Hospital Padre Américo 210, Guilhufe, 4564-007, Penafiel, Portugal.
| | - Catarina Cidade-Rodrigues
- Endocrinology Department, Centro Hospitalar do Tâmega e Sousa, Avenida Do Hospital Padre Américo 210, Guilhufe, 4564-007, Penafiel, Portugal
| | - Catarina Elias
- Internal Medicine Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
| | - Diana Oliveira
- Internal Medicine Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
| | - Paulo Bettencourt
- Medicine Faculty, Porto University, Porto, Portugal
- Internal Medicine Department, Hospital CUF Porto, Porto, Portugal
| | - Patrícia Lourenço
- Internal Medicine Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
- Medicine Faculty, Porto University, Porto, Portugal
- Heart Failure Clinic of the Internal Medicine Department, Centro Hospitalar e Universitário de São João, Porto, Portugal
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23
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Xiong Z, Xie P, Li J, Chen ZC, Lin Y, Liu M, Zhang S, Zhong X, Zhou H, Zhuang X, Liao X. Visit-to-Visit Fasting Glucose Variability in Young Adulthood and Cardiac Structure and Function at Midlife: The CARDIA Study. Front Cardiovasc Med 2021; 8:687054. [PMID: 34604347 PMCID: PMC8481606 DOI: 10.3389/fcvm.2021.687054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 06/21/2021] [Indexed: 11/13/2022] Open
Abstract
Glycemic variability was found associated with left ventricular structure and function in type 2 diabetes. But it is still unclear that whether the greater visit-to-visit fasting glucose (FG) variability in young adulthood among the community population is associated with cardiac function alteration and cardiac remodeling at midlife. The community-based prospective cohort study of Coronary Artery Risk in Young Adult (CARDIA) recruited young participants at the baseline age of 18-30 years during the period of 1985-1986 (Year 0). FG was measured at Year 0, 2, 10, 15, 20, and 25. The echocardiographic evaluation of cardiac structure and function was conducted at year 25. A total of 2,600 young adults mean (SD) aged at 24.9 years (3.6) of which 57.3% were women and 46.7% were African Americans had been included in the study. After multivariable adjusted, higher SD of mean FG (SDFG) is associated with lower early peak diastolic septal mitral annular velocity (e') (β [SE], -0.214 [0.080], P < 0.01) and higher E/e' (β [SE], 0.307 [0.094], P < 0.01), and higher coefficient of variation of the mean FG (CVFG) is also associated with lower e' (β [SE], -0.141[0.066], P < 0.05) and higher E/e' (β [SE], 0.204 [0.078], P < 0.01). The higher average real variation of mean FG (ARVFG) is associated with higher E/e' (β [SE], 0.178 [0.085], P < 0.05) and higher left ventricular mass index (LVMI) (β [SE], 1.240 [0.618], P < 0.05). The higher FG variability in young adulthood is associated with the subclinical change of left ventricular (LV) diastolic function at midlife.
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Affiliation(s)
- Zhenyu Xiong
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Peihan Xie
- Department of Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaying Li
- Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Zhi-chong Chen
- Cardiovascular Department, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yifen Lin
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Menghui Liu
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Shaozhao Zhang
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Xiangbin Zhong
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Huimin Zhou
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
| | - Xiaodong Zhuang
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
- Center for Information Technology and Statistics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinxue Liao
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China
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24
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Can Resistance Exercise Be a Tool for Healthy Aging in Post-Menopausal Women with Type 1 Diabetes? INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18168716. [PMID: 34444464 PMCID: PMC8393224 DOI: 10.3390/ijerph18168716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/12/2021] [Accepted: 08/15/2021] [Indexed: 11/25/2022]
Abstract
Due to improvements in diabetes care, people with type 1 diabetes (T1D) are living longer. Studies show that post-menopausal T1D women have a substantially elevated cardiovascular risk compared to those without T1D. As T1D may also accelerate age-related bone and muscle loss, the risk of frailty may be considerable for T1D women. Exercise and physical activity may be optimal preventative therapies to maintain health and prevent complications in this population: They are associated with improvements in, or maintenance of, cardiovascular health, bone mineral density, and muscle mass in older adults. Resistance exercise, in particular, may provide important protection against age-related frailty, due to its specific effects on bone and muscle. Fear of hypoglycemia can be a barrier to exercise in those with T1D, and resistance exercise may cause less hypoglycemia than aerobic exercise. There are currently no exercise studies involving older, post-menopausal women with T1D. As such, it is unknown whether current guidelines for insulin adjustment/carbohydrate intake for activity are appropriate for this population. This review focuses on existing knowledge about exercise in older adults and considers potential future directions around resistance exercise as a therapeutic intervention for post-menopausal T1D women.
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25
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Faienza MF, Scicchitano P, Lamparelli R, Zaza P, Cecere A, Brunetti G, Cortese F, Valente F, Delvecchio M, Giordano P, Zito AP, D'Amato G, Ciccone MM. Vascular and Myocardial Function in Young People with Type 1 Diabetes Mellitus: Insulin Pump Therapy Versus Multiple Daily Injections Insulin Regimen. Exp Clin Endocrinol Diabetes 2021; 130:415-422. [PMID: 34384121 DOI: 10.1055/a-1523-7574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) are two modalities of treating type 1 diabetes mellitus (T1DM). The benefits of CSII on long-term metabolic control and outcomes compared to those of MDI are still debated. We investigated both vascular function and myocardial performance in T1DM adolescents on MDI or CSII treatment. METHODS One hundred twenty-three T1DM subjects (mean age 14.16±2.55 years), 63 on MDI regimen, 60 on CSII, and 57 controls were enrolled. Anthropometric and biochemical characteristics were evaluated. Ultrasound assessments of carotid intima-media thickness (cIMT), flow-mediated dilatation of brachial artery, anteroposterior diameter of the infrarenal abdominal aorta (APAO), and transthoracic echocardiography were performed. RESULTS T1DM subjects on the CSII regimen showed better glycemic control than those on MDI, expressed as glycated haemoglobin (HbA1c). c-IMT and APAO were higher in MDI than CSII patients (0.61±0.11 mm vs. 0.56±0.07 mm, p=0.04; 13.61±3.29 mm vs. 11.65±1.84 mm, p=0.01, respectively). Left and right Tei index and left E/e' ratio were higher in MDI than CSII subjects (0.82±0.40 vs. 0.52±0.19, p=0.002; 0.86±0.41 vs. 0.64±0.1, p=0.02; 5.89±2.0 vs. 4.73±1.59, p=0.02, respectively). Multiple regression analyses showed that glucose level, HbA1c and diabetes onset were significantly related to vascular and echocardiographic parameters in MDI and CSII patients. CONCLUSIONS CSII regimen in T1DM adolescents improves glycemic control and seems to ameliorate endothelial function and global myocardial performance as compared to MDI therapy.
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Affiliation(s)
- Maria Felicia Faienza
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A.Moro", Bari, Italy
| | - Pietro Scicchitano
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
| | - Raffaella Lamparelli
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A.Moro", Bari, Italy
| | - Pierlugi Zaza
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A.Moro", Bari, Italy
| | - Annagrazia Cecere
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University "A. Moro" of Bari, Bari, Italy
| | - Francesca Cortese
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
| | - Federica Valente
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
| | - Maurizio Delvecchio
- Metabolic Diseases, Clinical Genetics and Diabetology Unit, Giovanni XXIII Children's Hospital, Bari, Italy
| | - Paola Giordano
- Department of Biomedical Sciences and Human Oncology, Pediatric Section, University "A.Moro", Bari, Italy
| | - Anna Paola Zito
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
| | - Gabriele D'Amato
- Department of Women's and Children's Health, ASL Bari, Neonatal Intensive Care Unit, "Di Venere" Hospital, Bari, Italy
| | - Marco Matteo Ciccone
- Section of Cardiovascular Diseases, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Bari, Italy
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Darvishi B, Dinarvand R, Mohammadpour H, Kamarul T, Sharifi AM. Dual l-Carnosine/ Aloe vera Nanophytosomes with Synergistically Enhanced Protective Effects against Methylglyoxal-Induced Angiogenesis Impairment. Mol Pharm 2021; 18:3302-3325. [PMID: 34297586 DOI: 10.1021/acs.molpharmaceut.1c00248] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Microvascular complications are among the major outcomes of patients with type II diabetes mellitus, which are the consequences of impaired physiological functioning of small blood vessels and angiogenic responses in these patients. Overproduction and accumulation of methylglyoxal (MGO), a highly reactive dicarbonyl byproduct of glycolysis pathway, has been acclaimed as the main inducer of impaired angiogenic responses and microvascular dysfunction in diabetic patients with uncontrolled hyperglycemia. Hence, an effective approach to overcome diabetes-associated microvascular complications is to neutralize the deleterious activity of enhanced the concentration of MGO in the body. Owing to the glycation inhibitory activity of Aloe vera whole extract, and capability of l-carnosine, an endogenous dipeptide, in attenuating MGO's destructive activity, we examined whether application of a combination of l-carnosine and A. vera could be an effective way of synergistically weakening this reactive dicarbonyl's impaired angiogenic effects. Additionally, overcoming the poor cellular uptake and internalization of l-carnosine and A. vera, a nanophytosomal formulation of the physical mixture of two compounds was also established. Although l-carnosine and A. vera at whole studied combination ratios could synergistically enhance viability of human umbilical vein endothelial cells (HUVECs) treated with MGO, the 25:1 w/w ratio was the most effective one among the others (27 ± 0.5% compared to 12 ± 0.3 to 18 ± 0.4%; F (4, 15) = 183.9, P < 0.0001). Developing dual nanophytosomes of l-carnosine/A. vera (25:1) combination ratio, we demonstrated superiority of the nanophytosomal formulation in protecting HUVECs against MGO-induced toxicity following a 24-72 h incubation period (17.3, 15.8, and 12.4% respectively). Moreover, 500 μg/mL concentration of dual l-carnosine/A. vera nanophytosomes exhibited a superior free radical scavenging potency (63 ± 4 RFU vs 83 ± 5 RFU; F (5, 12) = 54.81, P < 0.0001) and nitric oxide synthesizing capacity (26.11 ± 0.19 vs 5.1 ± 0.33; F (5, 12) = 2537, P < 0.0001) compared to their physical combination counterpart. Similarly, 500 μg/mL dual l-carnosine/A. vera nanophytosome-treated HUVECs demonstrated a superior tube formation capacity (15 ± 3 vs 2 ± 0.3; F (5, 12) = 30.87, P < 0.001), wound scratch healing capability (4.92 ± 0.3 vs 3.07 ± 0.3 mm/h; F (5, 12) = 39.21, P < 0.0001), and transwell migration (586 ± 32 vs 394 ± 18; F (5, 12) = 231.8, P < 0.001) and invasion (172 ± 9 vs 115 ± 5; F (5, 12) = 581.1, P < 0.0001) activities compared to the physical combination treated ones. Further confirming the proangiogenic activity of the dual l-carnosine/A. vera nanophytosomes, a significant shift toward expression of proangiogenic genes including HIF-1α, VEGFA, bFGF, KDR, and Ang II was reported in treated HUVECs. Overall, dual l-carnosine/A. vera nanophytosomes could be a potential candidate for attenuating type II DM-associated microvascular complications with an impaired angiogenesis background.
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Affiliation(s)
- Behrad Darvishi
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran.,Razi Drug Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Rassoul Dinarvand
- Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14155-6451, Iran.,Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 13169-43551, Iran
| | - Hadiseh Mohammadpour
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran 14155-5583, Iran
| | - Tunku Kamarul
- Tissue Engineering Group, (NOCERAL), Department of Orthopedic Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Ali Mohammad Sharifi
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran.,Razi Drug Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran.,Tissue Engineering Group, (NOCERAL), Department of Orthopedic Surgery, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.,Stem cell and Regenerative Medicine research center, Iran University of Medical Sciences, Tehran 1449614535, Iran
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Klimontov VV, Saik OV, Korbut AI. Glucose Variability: How Does It Work? Int J Mol Sci 2021; 22:ijms22157783. [PMID: 34360550 PMCID: PMC8346105 DOI: 10.3390/ijms22157783] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/07/2023] Open
Abstract
A growing body of evidence points to the role of glucose variability (GV) in the development of the microvascular and macrovascular complications of diabetes. In this review, we summarize data on GV-induced biochemical, cellular and molecular events involved in the pathogenesis of diabetic complications. Current data indicate that the deteriorating effect of GV on target organs can be realized through oxidative stress, glycation, chronic low-grade inflammation, endothelial dysfunction, platelet activation, impaired angiogenesis and renal fibrosis. The effects of GV on oxidative stress, inflammation, endothelial dysfunction and hypercoagulability could be aggravated by hypoglycemia, associated with high GV. Oscillating hyperglycemia contributes to beta cell dysfunction, which leads to a further increase in GV and completes the vicious circle. In cells, the GV-induced cytotoxic effect includes mitochondrial dysfunction, endoplasmic reticulum stress and disturbances in autophagic flux, which are accompanied by reduced viability, activation of apoptosis and abnormalities in cell proliferation. These effects are realized through the up- and down-regulation of a large number of genes and the activity of signaling pathways such as PI3K/Akt, NF-κB, MAPK (ERK), JNK and TGF-β/Smad. Epigenetic modifications mediate the postponed effects of glucose fluctuations. The multiple deteriorative effects of GV provide further support for considering it as a therapeutic target in diabetes.
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Affiliation(s)
- Vadim V. Klimontov
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia; (O.V.S.); (A.I.K.)
- Correspondence:
| | - Olga V. Saik
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia; (O.V.S.); (A.I.K.)
- Laboratory of Computer Proteomics, Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences (IC&G SB RAS), 630090 Novosibirsk, Russia
| | - Anton I. Korbut
- Laboratory of Endocrinology, Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia; (O.V.S.); (A.I.K.)
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Grassi B, Onetto MT, Zapata Y, Jofré P, Echeverría G. Lower versus standard sucrose dose for treating hypoglycemia in patients with type 1 diabetes mellitus in therapy with predictive low glucose suspend (PLGS) augmented insulin pumps: A randomized crossover trial in Santiago, Chile. Diabetes Metab Syndr 2021; 15:695-701. [PMID: 33813244 DOI: 10.1016/j.dsx.2021.03.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/17/2021] [Accepted: 03/18/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND AND AIMS Recommended hypoglycemia treatment in adults with T1D consists of 15 g of rapid absorption carbohydrates. We aimed to evaluate the response to fewer carbohydrates for treating hypoglycemia in patients with T1D on insulin pumps with predictive suspension technology (PLGS). METHODS T1D patients on insulin pumps with PLGS were randomized to receive 10 or 15 g of sucrose per hypoglycemia for two weeks (S10 and S15 groups, respectively) when capillary blood glucose (BG) was <70 mg/dL, with crossover after two weeks. Evolution of capillary BG, active insulin, and suspension time were assessed. RESULTS 59 hypoglycemic episodes were analyzed, 33 in S10 and 26 in S15. Baseline BG in S10 was 54.3 ± 7.7 mg/dL versus 56.9 ± 8.8 in S15 (p = 0,239). Active insulin, present in 85% of the episodes, and PLGS suspension time were similar between groups. BG at 15 min was 77 mg/dL in S10 and 95 mg/dL in S15 (p = 0.0007). In S10, 21% of the episodes required to repeat the treatment after 15 min compared with none on S15, with a RR of 0,79 (95% CI 0.66, 0.940, p = 0,014) for successfully treating the episode. Sensor glucose was significantly different from BG at the moment of the hypoglycemia and control 15 min after treatment. No severe hypoglycemia and no rebound hyperglycemia occurred in neither group. CONCLUSIONS A hypoglycemia treatment protocol with a lower dose of sucrose might be insufficient despite PLGS technology. Our data suggest that standard doses of sucrose should still be recommended.
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Affiliation(s)
- Bruno Grassi
- Departament of Nutrition, Diabetes and Metabolism, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile.
| | - María Teresa Onetto
- Departament of Nutrition, Diabetes and Metabolism, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Yazmín Zapata
- Departament of Nutrition, Diabetes and Metabolism, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Paulina Jofré
- Departament of Nutrition, Diabetes and Metabolism, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Guadalupe Echeverría
- Departament of Nutrition, Diabetes and Metabolism, School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile; Center of Molecular Nutrition and Chronic Diseases. School of Medicine. Pontificia Universidad Católica de Chile, Santiago, Chile
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Cindro PV, Krnić M, Modun D, Smajić B, Vuković J. The differences between insulin glargine U300 and insulin degludec U100 in impact on the glycaemic variability, arterial stiffness and the lipid profiles in insulin naïve patients suffering from type two diabetes mellitus - outcomes from cross-over open-label randomized trial. BMC Endocr Disord 2021; 21:86. [PMID: 33926446 PMCID: PMC8082786 DOI: 10.1186/s12902-021-00746-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND AND AIMS Diabetes mellitus type two is one of the major cardiovascular risk factors. Treatment of diabetes can reduce this risk, but the treatment options differ a lot in their risk-reducing capabilities. We compared the impact of insulin degludec (IDeg-100) and insulin glargine U300 (IGlar-300) on cardiovascular risk parameters - glycaemic variability (GV), arterial stiffness and lipid parameters - in insulin naive patients with DMT2. METHODS To 23 individuals who previously had uncontrolled DMT2 on two or more oral antidiabetic drugs, IGlar-300 and IDeg-100 were applied for 12 weeks and then switched in a cross over design manner. Prior and after of each insulin phase, we analysed biochemical parameters,7-point SMBG profile over three days and arterial stiffness which was assessed indirectly by measuring the augmentation index (AIx) on the principles of applanation tonometry. RESULTS There were no significant differences between IGlar-300 and IDeg-100 regarding reduction of mean glucose values and coefficient of variation (CV). Both insulins insignificantly reduced AIx for standardised pulse of 75 beats/min and without differences between them. IGlar-300 and IDeg-100 reduced triglycerides and increased HDL with no significant difference between the two insulins. IGlar-300 increased the total cholesterol level and IDeg-100 decreased total cholesterol, but without statistically significant difference. IGlar-300 increased LDL level by 0.508 mmol/L and IDeg-100 decreased LDL by 0.217 mmol/L, with statistically significant difference (p = 0.0215). CONCLUSIONS This study did not show significant difference between IGlar-300 and IDeg-100 regarding glycaemic parameters and augmentation index using the same dose of 0.2 IU/kg for both insulins, but it has revealed possible differences in impact on lipid profile. TRIAL REGISTRATION Clinicaltrials.gov, NCT04692415 . Retrospectively registered on December 31th 2020.
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Affiliation(s)
- Pavle Vrebalov Cindro
- Department of Gastroenterology, University Hospital Split, Spinčićeva 1, 21000, Split, Croatia
| | - Mladen Krnić
- Department of Endocrinology, University Hospital Split, Šoltanska 1, 21000, Split, Croatia.
- Department of Pathophysiology, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia.
| | - Darko Modun
- Department of Pharmacy, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Božo Smajić
- Medical Student, University of Split School of Medicine, Šoltanska 2, 21000, Split, Croatia
| | - Jonatan Vuković
- Department of Gastroenterology, University Hospital Split, Spinčićeva 1, 21000, Split, Croatia
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Katsiki N, Kotsa K, Stoian AP, Mikhailidis DP. Hypoglycaemia and Cardiovascular Disease Risk in Patients with Diabetes. Curr Pharm Des 2021; 26:5637-5649. [PMID: 32912117 DOI: 10.2174/1381612826666200909142658] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 08/09/2020] [Indexed: 12/12/2022]
Abstract
Hypoglycaemia represents an important side effect of insulin therapy and insulin secretagogues. It can occur in both type 1 and type 2 diabetes mellitus patients. Also, some associations between hypoglycaemia and cardiovascular (CV) risk have been reported. Several mechanisms may be involved, including the sympathoadrenal system, hypokalaemia, endothelial dysfunction, coagulation, platelets, inflammation, atherothrombosis and impaired autonomic cardiac reflexes. This narrative review discusses the associations of hypoglycaemia with CV diseases, including coronary heart disease (CHD), cardiac arrhythmias, stroke, carotid disease and peripheral artery disease (PAD), as well as with dementia. Severe hypoglycaemia has been related to CHD, CV and all-cause mortality. Furthermore, there is evidence supporting an association between hypoglycaemia and cardiac arrhythmias, potentially predisposing to sudden death. The data linking hypoglycaemia with stroke, carotid disease and PAD is limited. Several factors may affect the hypoglycaemia-CV relationships, such as the definition of hypoglycaemia, patient characteristics, co-morbidities (including chronic kidney disease) and antidiabetic drug therapy. However, the association between hypoglycaemia and dementia is bilateral. Both the disorders are more common in the elderly; thus, glycaemic goals should be carefully selected in older patients. Further research is needed to elucidate the impact of hypoglycaemia on CV disease.
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Affiliation(s)
- Niki Katsiki
- Division of Endocrinology and Metabolism, Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism, Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece
| | - Anca P Stoian
- Diabetes, Nutrition and Metabolic diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry, Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, United Kingdom
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Gómez AM, Henao-Carillo DC, Taboada L, Fuentes O, Lucero O, Sanko A, Robledo MA, Muñoz O, Rondón M, García-Jaramillo M, León-Vargas F. Clinical Factors Associated with High Glycemic Variability Defined by Coefficient of Variation in Patients with Type 2 Diabetes. MEDICAL DEVICES-EVIDENCE AND RESEARCH 2021; 14:97-103. [PMID: 33833594 PMCID: PMC8020138 DOI: 10.2147/mder.s288526] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/20/2021] [Indexed: 11/23/2022] Open
Abstract
Background High glycemic Variability (HGV) has become a stronger predictor of hypoglycemia. However, clinical factors associate with HGV still are unknown. Objective To determine clinical variables that were associated with a coefficient of variation (CV) above 36% evaluated by continuous glucose monitoring (CGM) in a group of patients with diabetes mellitus. Methods A cohort of patients with type 2 diabetes (T2D) was evaluated. Demographic variables, HbA1c, glomerular filtration rate (GFR) and treatment regimen were assessed. A bivariate analysis was performed, to evaluate the association between the outcome variable (CV> 36%) and each of the independent variables. A multivariate model was constructed to evaluate associations after controlling for confounding variables. Results CGM data from 274 patients were analyzed. CV> 36% was present in 56 patients (20.4%). In the bivariate analysis, demographic and clinical variables were included, such as time since diagnosis, hypoglycemia history, A1c, GFR and treatment established. In the multivariate analysis, GFR <45 mL/min (OR 2.81; CI 1.27,6.23; p:0.01), A1c > 9% (OR 2.81; CI 1.05,7.51; p:0.04) and hypoglycemia history (OR 2.09; CI 1.02,4.32; p:0.04) were associated with HGV. Treatment with iDPP4 (OR 0.39; CI 0.19,0.82; p:0.01) and AGLP1 (OR 0.08; CI 0.01,0.68; p:0.02) was inversely associated with GV. Conclusion Clinical variables such as GFR <45 mL/min, HbA1C>9% and a history of hypoglycemia are associated with a high GV. Our data suggest that the use of technology and treatments able to reduce glycemic variability could be useful in this population to reduce the risk of hypoglycemia and to improve glycemic control.
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Affiliation(s)
- A M Gómez
- Endocrinology Unit, Hospital Universitario San Ignacio, Bogotá, Colombia.,Department of Internal Medicine, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - D C Henao-Carillo
- Endocrinology Unit, Hospital Universitario San Ignacio, Bogotá, Colombia.,Department of Internal Medicine, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - L Taboada
- Endocrinology Unit, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - O Fuentes
- Endocrinology Unit, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - O Lucero
- Department of Internal Medicine, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - A Sanko
- Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - M A Robledo
- Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - O Muñoz
- Department of Internal Medicine, Hospital Universitario San Ignacio, Bogotá, Colombia.,Faculty of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - M Rondón
- Department of Clinical Epidemiology, Pontificia Universidad Javeriana, Bogotá, Colombia
| | | | - F León-Vargas
- Faculty of Engineering, Universidad Antonio Nariño, Bogotá, Colombia
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Garcia SM, Hirschberg PR, Sarkar P, Siegel DM, Teegala SB, Vail GM, Routh VH. Insulin actions on hypothalamic glucose-sensing neurones. J Neuroendocrinol 2021; 33:e12937. [PMID: 33507001 PMCID: PMC10561189 DOI: 10.1111/jne.12937] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/13/2022]
Abstract
Subsequent to the discovery of insulin 100 years ago, great strides have been made in understanding its function, especially in the brain. It is now clear that insulin is a critical regulator of the neuronal circuitry controlling energy balance and glucose homeostasis. This review focuses on the effects of insulin and diabetes on the activity and glucose sensitivity of hypothalamic glucose-sensing neurones. We highlight the role of electrophysiological data in understanding how insulin regulates glucose-sensing neurones. A brief introduction describing the benefits and limitations of the major electrophysiological techniques used to investigate glucose-sensing neurones is provided. The mechanisms by which hypothalamic neurones sense glucose are discussed with an emphasis on those glucose-sensing neurones already shown to be modulated by insulin. Next, the literature pertaining to how insulin alters the activity and glucose sensitivity of these hypothalamic glucose-sensing neurones is described. In addition, the effects of impaired insulin signalling during diabetes and the ramifications of insulin-induced hypoglycaemia on hypothalamic glucose-sensing neurones are covered. To the extent that it is known, we present hypotheses concerning the mechanisms underlying the effects of these insulin-related pathologies. To conclude, electrophysiological data from the hippocampus are evaluated aiming to provide clues regarding how insulin might influence neuronal plasticity in glucose-sensing neurones. Although much has been accomplished subsequent to the discovery of insulin, the work described in our review suggests that the regulation of central glucose sensing by this hormone is both important and understudied.
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Affiliation(s)
- Stephanie M Garcia
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pamela R Hirschberg
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Pallabi Sarkar
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Dashiel M Siegel
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Suraj B Teegala
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Gwyndolin M Vail
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
| | - Vanessa H Routh
- Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, The State University of New Jersey, Newark, NJ, USA
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Bellis A, Mauro C, Barbato E, Ceriello A, Cittadini A, Morisco C. Stress-Induced Hyperglycaemia in Non-Diabetic Patients with Acute Coronary Syndrome: From Molecular Mechanisms to New Therapeutic Perspectives. Int J Mol Sci 2021; 22:E775. [PMID: 33466656 PMCID: PMC7828822 DOI: 10.3390/ijms22020775] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 01/08/2023] Open
Abstract
Stress-induced hyperglycaemia (SIH) at hospital admission for acute coronary syndrome is associated with poor outcome, especially in patients without known diabetes. Nevertheless, insulin treatment in these subjects was not correlated with the reduction of mortality. This is likely due to the fact that SIH in the context of an acute coronary syndrome, compared to that in known diabetes, represents an epiphenomenon of other pathological conditions, such as adrenergic and renin-angiotensin system over-activity, hyperglucagonaemia, increase of circulating free fatty acids and pancreatic beta-cell dysfunction, which are not completely reversed by insulin therapy and so worsen the prognosis. Thus, SIH may be considered not only as a biomarker of organ damage, but also as an indicator of a more complex therapeutic strategy in these subjects. The aim of this review is to analyse the molecular mechanisms by which SIH may favour a worse prognosis in non-diabetic patients with acute coronary syndrome and identify new therapeutic strategies, in addition to insulin therapy, for a more appropriate treatment and improved outcomes.
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Affiliation(s)
- Alessandro Bellis
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy; (A.B.); (C.M.)
| | - Ciro Mauro
- Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy; (A.B.); (C.M.)
| | - Emanuele Barbato
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, 80131 Napoli, Italy;
| | - Antonio Ceriello
- Department of Cardiovascular and Metabolic Diseases, IRCCS Multimedica, Sesto San Giovanni, 20099 Milan, Italy;
| | - Antonio Cittadini
- Dipartimento di Scienze Mediche Traslazionali, Università Federico II, 80131 Napoli, Italy;
| | - Carmine Morisco
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, 80131 Napoli, Italy;
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La Sala L, Crestani M, Garavelli S, de Candia P, Pontiroli AE. Does microRNA Perturbation Control the Mechanisms Linking Obesity and Diabetes? Implications for Cardiovascular Risk. Int J Mol Sci 2020; 22:ijms22010143. [PMID: 33375647 PMCID: PMC7795227 DOI: 10.3390/ijms22010143] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/18/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metabolic disorders such as obesity and type 2 diabetes (T2D) are considered the major risk factors for the development of cardiovascular diseases (CVD). Although the pathological mechanisms underlying the mutual development of obesity and T2D are difficult to define, a better understanding of the molecular aspects is of utmost importance to identify novel therapeutic targets. Recently, a class of non-coding RNAs, called microRNAs (miRNAs), are emerging as key modulators of metabolic abnormalities. There is increasing evidence supporting the role of intra- and extracellular miRNAs as determinants of the crosstalk between adipose tissues, liver, skeletal muscle and other organs, triggering the paracrine communication among different tissues. miRNAs may be considered as risk factors for CVD due to their correlation with cardiovascular events, and in particular, may be related to the most prominent risk factors. In this review, we describe the associations observed between miRNAs expression levels and the most common cardiovascular risk factors. Furthermore, we sought to depict the molecular aspect of the interplay between obesity and diabetes, investigating the role of microRNAs in the interorgan crosstalk. Finally, we discussed the fascinating hypothesis of the loss of protective factors, such as antioxidant defense systems regulated by such miRNAs.
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Affiliation(s)
- Lucia La Sala
- Laboratory of Cardiovascular and Dysmetabolic Disease, IRCCS MultiMedica, 20138 Milan, Italy;
- Correspondence:
| | - Maurizio Crestani
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, 20133 Milan, Italy;
| | - Silvia Garavelli
- Laboratorio di Immunologia, Istituto per l’Endocrinologia e l’Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy;
| | - Paola de Candia
- Laboratory of Cardiovascular and Dysmetabolic Disease, IRCCS MultiMedica, 20138 Milan, Italy;
| | - Antonio E. Pontiroli
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy;
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Watt C, Sanchez-Rangel E, Hwang JJ. Glycemic Variability and CNS Inflammation: Reviewing the Connection. Nutrients 2020; 12:nu12123906. [PMID: 33371247 PMCID: PMC7766608 DOI: 10.3390/nu12123906] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 12/16/2022] Open
Abstract
Glucose is the primary energy source for the brain, and exposure to both high and low levels of glucose has been associated with numerous adverse central nervous system (CNS) outcomes. While a large body of work has highlighted the impact of hyperglycemia on peripheral and central measures of oxidative stress, cognitive deficits, and vascular complications in Type 1 and Type 2 diabetes, there is growing evidence that glycemic variability significantly drives increased oxidative stress, leading to neuroinflammation and cognitive dysfunction. In this review, the latest data on the impact of glycemic variability on brain function and neuroinflammation will be presented. Because high levels of oxidative stress have been linked to dysfunction of the blood-brain barrier (BBB), special emphasis will be placed on studies investigating the impact of glycemic variability on endothelial and vascular inflammation. The latest clinical and preclinical/in vitro data will be reviewed, and clinical/therapeutic implications will be discussed.
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He A, Hu S, Pi Q, Guo Y, Long Y, Luo S, Xia Y. Regulation of O-GlcNAcylation on endothelial nitric oxide synthase by glucose deprivation and identification of its O-GlcNAcylation sites. Sci Rep 2020; 10:19364. [PMID: 33168911 PMCID: PMC7652922 DOI: 10.1038/s41598-020-76340-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022] Open
Abstract
As an energy-sensitive post-translational modification, O-GlcNAcylation plays a major role in endothelial nitric oxide synthase (eNOS) activity regulation. However, effects of glucose deprivation on eNOS O-GlcNAcylation and the presence of novel O-GlcNAcylation sites of eNOS under glucose deprivation remain unknown. Hence, we aim to determine the effects of glucose deprivation on O-GlcNAcylation and novel O-GlcNAcylation sites of eNOS. Bovine aortic endothelial cells (BAECs) and Sprague-Dawley rats were induced by glucose deprivation and their eNOS O-GlcNAcylation was subjected to immunoblotting. eNOS and transfected eNOS were purified by pull-down assay and immunoprecipitation respectively. Novel O-GlcNAcylation sites of eNOS were predicted by HPLC-MS and MS/MS Ion and determined by immunoblotting. eNOS activity was detected by Elisa and isotope labeling method. In BAECs and rat thoracic aorta, low glucose-associated activation of eNOS was accompanied by elevated O-GlcNAcylation, which did not affect O-linked serine phosphorylation at 1179/1177 residues. Changes in this post-translational modification were associated with increased O-GlcNAc transferase (OGT) expression and were reversed by AMPK knockdown. Immunoblot analysis of cells expressing His-tagged wild-type human eNOS and human eNOS carrying a mutation at the Ser1177 phosphorylation site confirmed an increase in O-GlcNAcylation by glucose deprivation. A marked increase in O-GlcNAcylation indicated that eNOS contained novel O-GlcNAcylation sites that were activated by glucose deprivation. Immunoblot analysis of cells expressing His-tagged human eNOS carrying a mutation at Ser738 and Ser867 confirmed an increase in O-GlcNAcylation by glucose deprivation. Conversely, in His-tagged human eNOS carrying a mutation at Thr866, O-GlcNAcylation was unaffected by glucose deprivation. Differences in culture conditions were identified using two-way analysis of variance (ANOVA), one-way ANOVA, and unpaired Student's t-test. Glucose deprivation increases O-GlcNAcylation and activity of eNOS, potentially by the AMPK-OGT pathway, suggesting that Thr866 is a novel O-GlcNAcylation site involved in glucose-deprivation mediated eNOS activation.
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Affiliation(s)
- An He
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Shupeng Hu
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Qiangzhong Pi
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yongzheng Guo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yang Long
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Suxin Luo
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Xia
- Division of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China.
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Issar T, Tummanapalli SS, Kwai NCG, Chiang JCB, Arnold R, Poynten AM, Markoulli M, Krishnan AV. Associations between acute glucose control and peripheral nerve structure and function in type 1 diabetes. Diabet Med 2020; 37:1553-1560. [PMID: 32298478 DOI: 10.1111/dme.14306] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/09/2020] [Indexed: 12/13/2022]
Abstract
AIM To examine the associations between continuous overlapping net glycaemic action (CONGA), percentage time in hyperglycaemia (%HG) or normoglycaemia (%NG) and peripheral nerve structure and function in type 1 diabetes. METHODS Twenty-seven participants with type 1 diabetes underwent continuous glucose monitoring followed by corneal confocal microscopy and nerve excitability assessments. CONGA, %HG (> 10.0 mmol/l) and %NG (3.9-10.0 mmol/l) were correlated against corneal nerve fibre length and density in the central cornea and inferior whorl region, corneal microneuromas, and a nerve excitability score while controlling for age, sex, diabetes duration and HbA1c . RESULTS An increase in CONGA [median 2.5 (2.0-3.1) mmol/l] or %HG (mean 46 ± 18%) was associated with a worse nerve excitability score (r = -0.433, P = 0.036 and r = -0.670, P = 0.0012, respectively). By contrast, greater %NG (51 ± 17%) correlated with better nerve excitability scores (r = 0.672, P = 0.0011). Logistic regression revealed that increasing %HG increased the likelihood of abnormal nerve function [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01-1.23; P = 0.037). An increase in CONGA and %HG were associated with worsening nerve conduction measures, whereas longer %NG correlated with improved nerve conduction variables. CONGA and %HG were associated with inferior whorl corneal nerve fibre length (r = 0.483, P = 0.034 and r = 0.591, P = 0.021, respectively) and number of microneuromas (r = 0.433, P = 0.047 and r = 0.516, P = 0.020, respectively). CONCLUSIONS Short-term measures of glucose control are associated with impaired nerve function and alterations in corneal nerve morphology.
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Affiliation(s)
- T Issar
- Prince of Wales Clinical School, Sydney, NSW, Australia
| | - S S Tummanapalli
- School of Optometry & Vision Science, University of New South Wales, Sydney, NSW, Australia
| | - N C G Kwai
- Prince of Wales Clinical School, Sydney, NSW, Australia
- Department of Exercise Physiology, UNSW-Sydney, Sydney, NSW, Australia
| | - J C B Chiang
- School of Optometry & Vision Science, University of New South Wales, Sydney, NSW, Australia
| | - R Arnold
- Department of Exercise Physiology, UNSW-Sydney, Sydney, NSW, Australia
| | - A M Poynten
- Department of Endocrinology, Prince of Wales Hospital, Sydney, NSW, Australia
| | - M Markoulli
- School of Optometry & Vision Science, University of New South Wales, Sydney, NSW, Australia
| | - A V Krishnan
- Prince of Wales Clinical School, Sydney, NSW, Australia
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Jolink WMT, Wiegertjes K, Rinkel GJE, Algra A, de Leeuw FE, Klijn CJM. Location-specific risk factors for intracerebral hemorrhage: Systematic review and meta-analysis. Neurology 2020; 95:e1807-e1818. [PMID: 32690784 DOI: 10.1212/wnl.0000000000010418] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Accepted: 04/10/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE To conduct a systematic review and meta-analysis of studies reporting on risk factors according to location of the intracerebral hemorrhage. METHODS We searched PubMed and Embase for cohort and case-control studies reporting ≥100 patients with spontaneous intracerebral hemorrhage that specified the location of the hematoma and reported associations with risk factors published until June 27, 2019. Two authors independently extracted data on risk factors. Estimates were pooled with the generic variance-based random-effects method. RESULTS After screening 10,013 articles, we included 42 studies totaling 26,174 patients with intracerebral hemorrhage (9,141 lobar and 17,033 nonlobar). Risk factors for nonlobar intracerebral hemorrhage were hypertension (risk ratio [RR] 4.25, 95% confidence interval [CI] 3.05-5.91, I 2 = 92%), diabetes mellitus (RR 1.35, 95% CI 1.11-1.64, I 2 = 37%), male sex (RR 1.63, 95% CI 1.25-2.14, I 2 = 61%), alcohol overuse (RR 1.48, 95% CI 1.21-1.81, I 2 = 19%), underweight (RR 2.12, 95% CI 1.12-4.01, I 2 = 31%), and being a Black (RR 2.83, 95% CI 1.02-7.84, I 2 = 96%) or Hispanic (RR 2.95, 95% CI 1.69-5.14, I 2 = 71%) participant compared with being a White participant. Hypertension, but not any of the other risk factors, was also a risk factor for lobar intracerebral hemorrhage (RR 1.83, 95% CI 1.39-2.42, I 2 = 76%). Smoking, hypercholesterolemia, and obesity were associated with neither nonlobar nor lobar intracerebral hemorrhage. CONCLUSIONS Hypertension is a risk factor for both nonlobar and lobar intracerebral hemorrhage, although with double the effect for nonlobar intracerebral hemorrhage. Diabetes mellitus, male sex, alcohol overuse, underweight, and being a Black or Hispanic person are risk factors for nonlobar intracerebral hemorrhage only. Hence, the term hypertensive intracerebral hemorrhage for nonlobar intracerebral hemorrhage is not appropriate.
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Affiliation(s)
- Wilmar M T Jolink
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Kim Wiegertjes
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Gabriël J E Rinkel
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Ale Algra
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Frank-Erik de Leeuw
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Catharina J M Klijn
- From the Department of Neurology and Neurosurgery (W.M.T.J., G.J.E.R., A.A., C.J.M.K.) and Julius Center for Health Sciences and Primary Care (A.A.), University Medical Center Utrecht Brain Center, Utrecht University; and Department of Neurology (K.W., F.-E.d.L., C.J.M.K.), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
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Ceriello A, Standl E, Catrinoiu D, Itzhak B, Lalic NM, Rahelic D, Schnell O, Škrha J, Valensi P. Issues for the management of people with diabetes and COVID-19 in ICU. Cardiovasc Diabetol 2020; 19:114. [PMID: 32690029 PMCID: PMC7370631 DOI: 10.1186/s12933-020-01089-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 07/15/2020] [Indexed: 02/07/2023] Open
Abstract
In the pandemic “Corona Virus Disease 2019” (COVID-19) people with diabetes have a high risk to require ICU admission. The management of diabetes in Intensive Care Unit is always challenging, however, when diabetes is present in COVID-19 the situation seems even more complicated. An optimal glycemic control, avoiding acute hyperglycemia, hypoglycemia and glycemic variability may significantly improve the outcome. In this case, intravenous insulin infusion with continuous glucose monitoring should be the choice. No evidence suggests stopping angiotensin-converting-enzyme inhibitors, angiotensin-renin-blockers or statins, even it has been suggested that they may increase the expression of Angiotensin-Converting-Enzyme-2 (ACE2) receptor, which is used by “Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to penetrate into the cells. A real issue is the usefulness of several biomarkers, which have been suggested to be measured during the COVID-19. N-Terminal-pro-Brain Natriuretic-Peptide, D-dimer and hs-Troponin are often increased in diabetes. Their meaning in the case of diabetes and COVID-19 should be therefore very carefully evaluated. Even though we understand that in such a critical situation some of these requests are not so easy to implement, we believe that the best possible action to prevent a worse outcome is essential in any medical act.
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Affiliation(s)
- Antonio Ceriello
- IRCCS MultiMedica, Via Gaudenzio Fantoli, 16/15, 20138, Milan, Italy.
| | - Eberhard Standl
- Forschergruppe Diabetes e.V. at Munich Helmholtz Centre, Munich, Germany
| | - Doina Catrinoiu
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
| | - Baruch Itzhak
- Clalit Health Services and Technion Faculty of Medicine, Haifa, Israel
| | - Nebojsa M Lalic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dario Rahelic
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia.,University of Zagreb School of Medicine, Zagreb, Croatia.,University of Osijek School of Medicine, Osijek, Croatia
| | - Oliver Schnell
- Forschergruppe Diabetes e.V. at Munich Helmholtz Centre, Munich, Germany
| | - Jan Škrha
- Department of Internal Medicine 3, 1st Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Paul Valensi
- Unit of Endocrinology, Diabetology, Nutrition, Jean Verdier Hospital, APHP, Paris Nord University, Sorbonne Paris Cité, CINFO, CRNH-IdF, Bondy, France
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Ceriello A, Standl E, Catrinoiu D, Itzhak B, Lalic NM, Rahelic D, Schnell O, Škrha J, Valensi P. Issues of Cardiovascular Risk Management in People With Diabetes in the COVID-19 Era. Diabetes Care 2020; 43:1427-1432. [PMID: 32409501 DOI: 10.2337/dc20-0941] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 04/27/2020] [Indexed: 02/03/2023]
Abstract
People with diabetes compared with people without exhibit worse prognosis if affected by coronavirus disease 2019 (COVID-19) induced by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), particularly when compromising metabolic control and concomitant cardiovascular disorders are present. This Perspective seeks to explore newly occurring cardio-renal-pulmonary organ damage induced or aggravated by the disease process of COVID-19 and its implications for the cardiovascular risk management of people with diabetes, especially taking into account potential interactions with mechanisms of cellular intrusion of SARS-CoV-2. Severe infection with SARS-CoV-2 can precipitate myocardial infarction, myocarditis, heart failure, and arrhythmias as well as an acute respiratory distress syndrome and renal failure. They may evolve along with multiorgan failure directly due to SARS-CoV-2-infected endothelial cells and resulting endotheliitis. This complex pathology may bear challenges for the use of most diabetes medications in terms of emerging contraindications that need close monitoring of all people with diabetes diagnosed with SARS-CoV-2 infection. Whenever possible, continuous glucose monitoring should be implemented to ensure stable metabolic compensation. Patients in the intensive care unit requiring therapy for glycemic control should be handled solely by intravenous insulin using exact dosing with a perfusion device. Although not only ACE inhibitors and angiotensin 2 receptor blockers but also SGLT2 inhibitors, GLP-1 receptor agonists, pioglitazone, and probably insulin seem to increase the number of ACE2 receptors on the cells utilized by SARS-CoV-2 for penetration, no evidence presently exists that shows this might be harmful in terms of acquiring or worsening COVID-19. In conclusion, COVID-19 and related cardio-renal-pulmonary damage can profoundly affect cardiovascular risk management of people with diabetes.
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Affiliation(s)
| | - Eberhard Standl
- Forschergruppe Diabetes e.V. at Munich Helmholtz Centre, Munich, Germany
| | - Doina Catrinoiu
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
| | - Baruch Itzhak
- Clalit Health Services and Technion Faculty of Medicine, Haifa, Israel
| | - Nebojsa M Lalic
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dario Rahelic
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases, Merkur University Hospital, Zagreb, Croatia.,University of Zagreb School of Medicine, Zagreb, Croatia.,University of Osijek School of Medicine, Osijek, Croatia
| | - Oliver Schnell
- Forschergruppe Diabetes e.V. at Munich Helmholtz Centre, Munich, Germany
| | - Jan Škrha
- Department of Internal Medicine 3, First Faculty of Medicine, Charles University, Prague, Czech Republic
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Vecchié A, Montecucco F, Carbone F, Dallegri F, Bonaventura A. Diabetes and Vascular Disease: Is It All About Glycemia? Curr Pharm Des 2020; 25:3112-3127. [PMID: 31470783 DOI: 10.2174/1381612825666190830181944] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/24/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Diabetes is increasing over time, mainly driven by obesity, aging, and urbanization. Classical macro- and microvascular complications represent the final result of a complex interplay involving atherosclerosis at all stages. METHODS In this review, we aim at focusing on current updates in the pathophysiology of vascular disease in diabetes and discussing how new therapies might influence the management of these patients at high cardiovascular risk. Diabetes shows accelerated atherosclerosis with a larger inflammatory cell infiltrate, thus favoring the development of heart failure. 'Diabetic cardiomyopathy' perfectly describes a specific ischemia- and hypertension- independent entity due to diabetes-related metabolic alterations on myocardial function. Moreover, platelets from subjects with diabetes display a typical hyperreactivity explaining the stronger adhesion, activation, and aggregation. Additionally, diabetes provokes an exaggerated stimulation of the endothelium, with an increased release of reactive oxygen species and a reduced release of nitric oxide, both key elements of the endothelial dysfunction. Also, the coagulation cascade and leukocytes activate contributing to this pro-thrombotic environment. Neutrophils have been recently recognized to play a pivotal role by releasing neutrophil extracellular traps. Finally, microparticles from platelets, neutrophils or monocytes are detrimental effectors on the vessel wall and are involved both in vascular dysfunction and in thrombotic complications. CONCLUSION In light of these findings, the therapeutic management of diabetes needs to be mostly focused on limiting the progression of complications by targeting precise pathophysiological mechanisms rather than the mere glycemic control, which failed to markedly reduce the risk for macrovascular complications and mortality.
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Affiliation(s)
- Alessandra Vecchié
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.,Virginia Commonwealth University, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Richmond, Virginia, United States of America
| | - Fabrizio Montecucco
- First Clinic of Internal Medicine, Department of Internal Medicine and Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 6 Viale Benedetto XV, 16132 Genoa, Italy.,IRCCS Ospedale Policlinico San Martino Genova - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
| | - Federico Carbone
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.,IRCCS Ospedale Policlinico San Martino Genova - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
| | - Franco Dallegri
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.,IRCCS Ospedale Policlinico San Martino Genova - Italian Cardiovascular Network, 10 Largo Benzi, 16132 Genoa, Italy
| | - Aldo Bonaventura
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy.,Virginia Commonwealth University, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Richmond, Virginia, United States of America
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43
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Silk sericin has significantly hypoglycaemic effect in type 2 diabetic mice via anti-oxidation and anti-inflammation. Int J Biol Macromol 2020; 150:1061-1071. [DOI: 10.1016/j.ijbiomac.2019.10.111] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 09/26/2019] [Accepted: 10/10/2019] [Indexed: 11/19/2022]
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Yao RQ, Ren C, Wu GS, Zhu YB, Xia ZF, Yao YM. Is intensive glucose control bad for critically ill patients? A systematic review and meta-analysis. Int J Biol Sci 2020; 16:1658-1675. [PMID: 32226310 PMCID: PMC7097913 DOI: 10.7150/ijbs.43447] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 02/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background: The monitoring and management of blood glucose concentration are standard practices in critical settings as hyperglycaemia has been shown close association with poorer outcomes. Several meta-analyses have revealed that intensive glucose control has no benefit in decreasing short-term mortality among critically ill patients, while the studies these meta-analyses have incorporated have been largely divergent. We aim to perform a more comprehensive meta-analysis addressing this problem to provide stronger evidence. Methods: We conducted comprehensive searches for relevant randomized controlled studies in online databases, including the Cochrane Library, EMBASE, and PubMed databases, up to September 1, 2018. The clinical data, which included all-cause mortality, severe hypoglycemia, need for RRT, infection resulting in sepsis, ICU mortality, 90-day mortality, 180-day mortality, and hospital and ICU lengths of stay, were screened and analyzed after data extraction. We applied odds ratios (ORs) to analyze dichotomous outcomes and mean differences for continuous outcomes with a random effects model. Results: A total of 57 RCTs involving a total of 21840 patients were finally included. Patients admitted to the ICU who underwent intensive glucose control showed significantly reduced all-cause mortality (OR: 0.89; 95% CI: 0.80-1.00; P=0.04; I2=32%), reduced infection rate (OR: 0.65, 95% CI: 0.51-0.82, P=0.0002; I2=47%), a lower occurrence of acquired sepsis (OR: 0.80, 95% CI: 0.65-0.99, P=0.04; I2=0%) and shortened length of ICU stay (MD: -0.70, 95% CI: -1.21--0.19, P=0.007, I2=70%) when compared to the same parameters as those treated with the usual care strategy. However, patients in the intensive glucose control group presented with a significantly higher risk of severe hypoglycemia (OR: 5.63, 95% CI: 4.02-7.87, P<0.00001; I2=67%). Conclusions: Critically ill patients undergoing intensive glucose control showed significantly reduced all-cause mortality, length of ICU stay and incidence of acquired infection and sepsis compared to the same parameters in patients treated with the usual care strategy, while the intensive glucose control strategy was associated with higher occurrence of severe hypoglycemic events.
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Affiliation(s)
- Ren-qi Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, People's Republic of China
- Department of Burn Surgery, Changhai Hospital, the Second Military Medical University, Shanghai 200433, People's Republic of China
| | - Chao Ren
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, People's Republic of China
| | - Guo-sheng Wu
- Department of Burn Surgery, Changhai Hospital, the Second Military Medical University, Shanghai 200433, People's Republic of China
| | - Yi-bing Zhu
- Department of Critical Care Medicine, Fuxing Hospital, Capital Medical University, Beijing 100038, People's Republic of China
| | - Zhao-fan Xia
- Department of Burn Surgery, Changhai Hospital, the Second Military Medical University, Shanghai 200433, People's Republic of China
| | - Yong-ming Yao
- Trauma Research Center, Fourth Medical Center of the Chinese PLA General Hospital, Beijing 100048, People's Republic of China
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Momozono A, Kodera Y, Sasaki S, Nakagawa Y, Konno R, Shichiri M. Oxidised Met 147 of human serum albumin is a biomarker of oxidative stress, reflecting glycaemic fluctuations and hypoglycaemia in diabetes. Sci Rep 2020; 10:268. [PMID: 31937809 PMCID: PMC6959251 DOI: 10.1038/s41598-019-57095-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 12/20/2019] [Indexed: 11/17/2022] Open
Abstract
Oxidative stress has been linked to a number of chronic diseases, and this has aroused interest in the identification of clinical biomarkers that can accurately assess its severity. We used liquid chromatography-high resolution mass spectrometry (LC-MS) to show that oxidised and non-oxidised Met residues at position 147 of human serum albumin (Met147) can be accurately and reproducibly quantified with stable isotope-labelled peptides. Met147 oxidation was significantly higher in patients with diabetes than in controls. Least square multivariate analysis revealed that glycated haemoglobin (HbA1c) and glycated albumin (GA) did not significantly influence Met147 oxidation, but the GA/HbA1c ratio, which reflects glycaemic excursions, independently affected Met147 oxidation status. Continuous glucose monitoring revealed that Met147 oxidation strongly correlates with the standard deviation of sensor glucose concentrations and the time spent with hypoglycaemia or hyperglycaemia each day. Thus, glycaemic variability and hypoglycaemia in diabetes may be associated with greater oxidation of Met147. Renal function, high-density lipoprotein-cholesterol and serum bilirubin were also associated with the oxidation status of Met147. In conclusion, the quantification of oxidised and non-oxidised Met147 in serum albumin using our LC-MS methodology could be used to assess the degree of intravascular oxidative stress induced by hypoglycaemia and glycaemic fluctuations in diabetes.
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Affiliation(s)
- Akari Momozono
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.,Department of Physics and Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.,Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Yoshio Kodera
- Department of Physics and Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.,Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Sayaka Sasaki
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.,Department of Physics and Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan.,Center for Disease Proteomics, Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Yuzuru Nakagawa
- Department of Physics and Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Ryo Konno
- Department of Physics and Kitasato University School of Science, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan
| | - Masayoshi Shichiri
- Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
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Papachristoforou E, Lambadiari V, Maratou E, Makrilakis K. Association of Glycemic Indices (Hyperglycemia, Glucose Variability, and Hypoglycemia) with Oxidative Stress and Diabetic Complications. J Diabetes Res 2020; 2020:7489795. [PMID: 33123598 PMCID: PMC7585656 DOI: 10.1155/2020/7489795] [Citation(s) in RCA: 204] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/16/2020] [Accepted: 09/23/2020] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress (OS) is defined as a disturbance in the prooxidant-antioxidant balance of the cell, in favor of the former, which results in the antioxidant capacity of the cell to be overpowered. Excess reactive oxygen species (ROS) production is very harmful to cell constituents, especially proteins, lipids, and DNA, thus causing damage to the cell. Oxidative stress has been associated with a variety of pathologic conditions, including diabetes mellitus (DM), cancer, atherosclerosis, neurodegenerative diseases, rheumatoid arthritis, ischemia/reperfusion injury, obstructive sleep apnea, and accelerated aging. Regarding DM specifically, previous experimental and clinical studies have pointed to the fact that oxidative stress probably plays a major role in the pathogenesis and development of diabetic complications. It is postulated that hyperglycemia induces free radicals and impairs endogenous antioxidant defense systems through several different mechanisms. In particular, hyperglycemia promotes the creation of advanced glycation end-products (AGEs), the activation of protein kinase C (PKC), and the hyperactivity of hexosamine and sorbitol pathways, leading to the development of insulin resistance, impaired insulin secretion, and endothelial dysfunction, by inducing excessive ROS production and OS. Furthermore, glucose variability has been associated with OS as well, and recent evidence suggests that also hypoglycemia may be playing an important role in favoring diabetic vascular complications through OS, inflammation, prothrombotic events, and endothelial dysfunction. The association of these diabetic parameters (i.e., hyperglycemia, glucose variability, and hypoglycemia) with oxidative stress will be reviewed here.
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Affiliation(s)
- Eleftheria Papachristoforou
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Laiko General Hospital, Athens, Greece
| | - Vaia Lambadiari
- Second Department of Internal Medicine, Research Unit and Diabetes Centre, National and Kapodistrian University of Athens Medical School, Attikon Hospital, Athens, Greece
| | - Eirini Maratou
- Second Department of Internal Medicine, Research Unit and Diabetes Centre, National and Kapodistrian University of Athens Medical School, Attikon Hospital, Athens, Greece
| | - Konstantinos Makrilakis
- First Department of Propaedeutic Internal Medicine, National and Kapodistrian University of Athens Medical School, Laiko General Hospital, Athens, Greece
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Lespagnol E, Dauchet L, Pawlak-Chaouch M, Balestra C, Berthoin S, Feelisch M, Roustit M, Boissière J, Fontaine P, Heyman E. Early Endothelial Dysfunction in Type 1 Diabetes Is Accompanied by an Impairment of Vascular Smooth Muscle Function: A Meta-Analysis. Front Endocrinol (Lausanne) 2020; 11:203. [PMID: 32362871 PMCID: PMC7180178 DOI: 10.3389/fendo.2020.00203] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/23/2020] [Indexed: 12/15/2022] Open
Abstract
Background: A large yet heterogeneous body of literature exists suggesting that endothelial dysfunction appears early in type 1 diabetes, due to hyperglycemia-induced oxidative stress. The latter may also affect vascular smooth muscles (VSM) function, a layer albeit less frequently considered in that pathology. This meta-analysis aims at evaluating the extent, and the contributing risk factors, of early endothelial dysfunction, and of the possible concomitant VSM dysfunction, in type 1 diabetes. Methods: PubMed, Web of Sciences, Cochrane Library databases were screened from their respective inceptions until October 2019. We included studies comparing vasodilatory capacity depending or not on endothelium (i.e., endothelial function or VSM function, respectively) in patients with uncomplicated type 1 diabetes and healthy controls. Results: Fifty-eight articles studying endothelium-dependent function, among which 21 studies also assessed VSM, were included. Global analyses revealed an impairment of standardized mean difference (SMD) (Cohen's d) of endothelial function: -0.61 (95% CI: -0.79, -0.44) but also of VSM SMD: -0.32 (95% CI: -0.57, -0.07). The type of stimuli used (i.e., exercise, occlusion-reperfusion, pharmacological substances, heat) did not influence the impairment of the vasodilatory capacity. Endothelial dysfunction appeared more pronounced within macrovascular than microvascular beds. The latter was particularly altered in cases of poor glycemic control [HbA1c > 67 mmol/mol (8.3%)]. Conclusions: This meta-analysis not only corroborates the presence of an early impairment of endothelial function, even in response to physiological stimuli like exercise, but also highlights a VSM dysfunction in children and adults with type 1 diabetes. Endothelial dysfunction seems to be more pronounced in large than small vessels, fostering the debate on their relative temporal appearance.
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Affiliation(s)
- Elodie Lespagnol
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Lille, France
| | - Luc Dauchet
- Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France
| | - Mehdi Pawlak-Chaouch
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Lille, France
| | - Costantino Balestra
- Environmental and Occupational (Integrative) Physiology Laboratory, Haute École Bruxelles-Brabant HE2B, Brussels, Belgium
| | - Serge Berthoin
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Lille, France
| | - Martin Feelisch
- Clinical and Experimental Sciences, Faculty of Medicine, University Hospital Southampton NHS Foundation Trust, University of Southampton, Southampton, United Kingdom
| | - Matthieu Roustit
- Univ. Grenoble Alpes, HP2, Inserm, CHU Grenoble Alpes, Grenoble, France
| | - Julien Boissière
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Lille, France
| | - Pierre Fontaine
- Département d'endocrinologie, Diabète et maladies métaboliques, Hôpital Huriez, Université de Lille, Lille, France
| | - Elsa Heyman
- Univ. Lille, Univ. Artois, Univ. Littoral Côte d'Opale, ULR 7369 - URePSSS - Unité de Recherche Pluridisciplinaire Sport Santé Société, Lille, France
- *Correspondence: Elsa Heyman
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Martyn-Nemeth P, Duffecy J, Quinn L, Park C, Mihailescu D, Penckofer S. A cognitive behavioral therapy intervention to reduce fear of hypoglycemia in young adults with type 1 diabetes (FREE): study protocol for a randomized controlled trial. Trials 2019; 20:796. [PMID: 31888691 PMCID: PMC6938021 DOI: 10.1186/s13063-019-3876-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 11/02/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND In persons with type 1 diabetes (T1D), hypoglycemia is the major limiting factor in achieving optimal glycemic control. All persons with T1D are at risk for hypoglycemia (blood glucose level < 70 mg/dl), which is life-threatening and accompanied by serious physical and psychological symptoms, resulting in profound fear of hypoglycemia (FOH) and reduced quality of life. Young adults with T1D are at risk for FOH and have worse glycemic control and self-management behavior than other age groups with T1D. FOH also results in increased glycemic variability (GV). A major gap exists in how to manage FOH. Our overall objective is to reduce FOH and improve diabetes self-management, glycemic control, and GV in young adults with T1D to reduce or delay diabetes complications and improve quality of life. We aim to (1) determine the feasibility and acceptability of an eight-week cognitive behavioral therapy (CBT)-based Fear Reduction Efficacy Evaluation (FREE) intervention in young adults with T1D who experience FOH; and (2) determine the impact of the FREE intervention, compared to an attention control group, on the outcomes FOH, self-management, glycemic control (A1C), and glycemic variability (continuous glucose monitoring recordings). METHODS/DESIGN A randomized controlled trial in 50 young adults aged 18 to 35 years with T1D will be used. Eligible subjects will be randomized to the intervention program (Fear Reduction Efficacy Evaluation [FREE]) or attention control group. A one-week run-in phase is planned, with baseline measures of FOH, self-management behavior, A1C, and real-time continuous glucose monitoring recordings (RT-CGM) to calculate GV for both groups. The intervention group will participate in eight weekly individual one-hour sessions using CBT and exposure treatment for specific fears. RT-CGM and a daily FOH diary will be used as feedback cues as part of the FREE program. The attention control group will participate in eight weekly individual one-hour diabetes self-management education (DSME) sessions and wear a RT-CGM device (to measure GV only) over 8 weeks. At completion, FOH will be measured, and RT-CGM recordings will be analyzed to determine differences between the FREE and control groups. DISCUSSION Findings from this proposed pilot study will serve as the foundation for a larger trial to reduce FOH and improve self-management, glycemic control, and GV. TRIAL REGISTRATION ClinicalTrials.gov: A cognitive behavioral therapy (CBT) intervention to reduce fear of hypoglycemia in type 1 diabetes, NCT03549104. Registered June 7, 2018.
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Affiliation(s)
- Pamela Martyn-Nemeth
- Department of Biobehavioral Health Science, University of Illinois at Chicago College of Nursing, 845 South Damen Avenue (MC 802), Chicago, IL, 60612, USA.
| | - Jennifer Duffecy
- Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA
| | - Laurie Quinn
- Department of Biobehavioral Health Science, University of Illinois at Chicago College of Nursing, 845 South Damen Avenue (MC 802), Chicago, IL, 60612, USA
| | - Chang Park
- Department of Health Systems Science, University of Illinois at Chicago College of Nursing, Chicago, IL, USA
| | - Dan Mihailescu
- Endocrinology/Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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Ohara M, Hiromura M, Nagaike H, Kohata Y, Fujikawa T, Goto S, Sato N, Kushima H, Terasaki M, Yamamoto T, Mori Y, Hayashi T, Fukui T, Yamagishi SI, Hirano T. Relationship between glucose variability evaluated by continuous glucose monitoring and clinical factors, including glucagon-stimulated insulin secretion in patients with type 2 diabetes. Diabetes Res Clin Pract 2019; 158:107904. [PMID: 31672500 DOI: 10.1016/j.diabres.2019.107904] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 08/30/2019] [Accepted: 10/25/2019] [Indexed: 12/24/2022]
Abstract
AIMS To evaluate the clinical factors affecting daily and day-to-day glucose variability by using continuous glucose monitoring. METHODS We performed a cross-sectional analysis of patients with type 2 diabetes mellitus (T2DM) who underwent a glucagon stimulation test (GST) with 72 h of continuous glucose monitoring. Daily glucose variability was evaluated by mean amplitude of glycemic excursions [MAGE], percentage coefficient of variation for glucose (%CV), and day-to-day glucose variability (mean of daily differences [MODD]) by using continuous glucose monitoring. Correlations of clinical factors, including insulin secretion ability by the GST with MAGE, %CV, and MODD, were analyzed. RESULTS In 83 T2DM with insulin therapy, age and hemoglobin A1c (HbA1c) correlated with MAGE and %CV, fasting plasma glucose with MAGE and MODD, and increment of C-peptide immunoreactivity (ΔCPR) by GST correlated inversely with MAGE, %CV, and MODD. In 126 T2DM without insulin therapy, age, diastolic blood pressure, and triglycerides correlated with MODD, HbA1c with MAGE and MODD, and ΔCPR inversely correlated with %CV. Use of α-glucosidase inhibitors inversely correlated with %CV, whereas that of sulfonylurea was associated with MAGE and %CV. CONCLUSIONS These results suggest that ΔCPR correlated with stability of glycemic control, whereas poorly controlled diabetes is associated with increase in glucose variability. α-glucosidase inhibitors may be superior to sulfonylureas in reducing the glucose variability in T2DM.
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Affiliation(s)
- Makoto Ohara
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
| | - Munenori Hiromura
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Hiroe Nagaike
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Yo Kohata
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Tomoki Fujikawa
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Satoshi Goto
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Nobuko Sato
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Hideki Kushima
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Michishige Terasaki
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Takeshi Yamamoto
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Yusaku Mori
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Toshiyuki Hayashi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Tomoyasu Fukui
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Sho-Ichi Yamagishi
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan
| | - Tsutomu Hirano
- Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan; Diabetes Center, Ebina General Hospital, Ebina, Japan
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Circulating Wnt1-inducible signaling pathway protein-1 (WISP-1/CCN4) is a novel biomarker of adiposity in subjects with type 2 diabetes. J Cell Commun Signal 2019; 14:101-109. [PMID: 31782053 DOI: 10.1007/s12079-019-00536-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Wnt1-inducible signaling pathway protein 1, or cellular communication network factor 4 (CCN4), a member of CCN family of secreted, extracellular matrix associated signaling proteins, recently was validated as a novel adipose tissue derived cytokine. OBJECTIVE To assess the relationships between circulating CCN4, adipose tissue distribution and function, and chronic low-grade inflammation in subjects with type 2 diabetes. METHODS We observed 156 patients with type 2 diabetes and 24 healthy controls. Serum levels of CCN4, hsCRP and alpha1-acid glycoprotein (alpha1-AGP) were measured by ELISA. Serum concentrations of leptin, resistin, visfatin, adipsin, adiponectin, IL-6, IL-8, IL-18 and TNF-alpha were determined by multiplex analysis. Fat mass and distribution was assessed by DEXA. Mean diameter of adipocytes was estimated in samples of subcutaneous adipose tissue. RESULTS Patients with diabetes had higher levels of circulating CCN4, leptin, resistin, adipsin, visfatin, hsCRP, alpha1-AGP, and IL-6 (all p < 0.02). The CCN4 concentration correlated positively with percentage of fat mass in central abdominal area, as well as with leptin, resistin and visfatin levels; negative correlation was found between CCN4 and mean adipocyte diameter. In multiple regression analysis fat mass in central abdominal area was independent predictor for CCN4 concentration. CONCLUSION In subjects with type 2 diabetes serum levels of CCN4 are associated with central abdominal fat mass and adipose tissue dysfunction.
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