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Barmpagianni A, Karamanakos G, Anastasiou IA, Kountouri A, Lambadiari V, Liatis S. The relationship between residual insulin secretion and subclinical cardiovascular risk indices in young adults with type 1 diabetes. J Diabetes Complications 2025; 39:108946. [PMID: 39731973 DOI: 10.1016/j.jdiacomp.2024.108946] [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: 06/07/2024] [Revised: 09/25/2024] [Accepted: 12/21/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND Patients with type 1 diabetes (DM1), even in the setting of adequate glycaemic control, have an excess risk for developing cardiovascular disease. Residual insulin secretion (RIS), measured by detectable C-peptide levels in patients with DM1, might protect against diabetes-related complications. This study aimed to examine the relationship between residual insulin secretion and prognostic markers of cardiovascular complications in patients with DM1. METHODS A total of 137 patients with DM1 were included in this analysis. They were of young age (<45 years), with an established diagnosis of over two years before the study entry and without a history of cardiovascular complications. All patients underwent complete clinical and laboratory evaluation. A c-peptide measurement of ≥0.05 ng/ml was used to identify the presence of RIS. Pulse wave velocity (PWV), cardiac autonomic function assessed both at rest, by total power of heart rate variability and dynamically, by the expiration to inspiration (e/i) index, albumin to creatinine ratio (ACR), and high sensitivity CRP (hs-CRP) were used as predictive biomarkers of cardiovascular complications. RESULTS Female participants represented 63.5% of the population [mean age: 29.7 (±8.1) years, mean HbA1c: 7.6% (±1.4), median diabetes duration:15 (10-21) years, median age at diabetes diagnosis: 13 (8-17) years]]. The median value of fasting c-peptide was 0.04 (0.03-0.05) ng/ml, and RIS was detected in 32 patients (23.4%). Patients with RIS had a shorter diabetes duration, an older age at diagnosis and a lower BMI, while no significant association was found between residual c-peptide and age or HbA1c. RIS was significantly associated with lower PWV values [8.1 m/s² (7-8.7) vs 9.2 m/s² (7.8-10.1), p <0,001], higher total power values [1124 Hz (600-3277) vs 577 Hz (207-2091), p <0,001], and higher E/I measurements [1.4 (1.2-1.5) vs. 1.3 (1.2-1.4), p=0.01]. No significant association was noted between RIS and either ACR or hs-CRP. In multivariable linear regression analysis, the association between RIS and lower PWV values remained significant (p= 0.007) regardless of age, sex, diabetes duration or age of diagnosis, blood pressure and BMI. Similarly, residual insulin secretion retained a significant independent association with total power (p= 0.032) and E/I (p=0.045). CONCLUSION In young patients with DM1, free of macrovascular complications, residual insulin secretion is independently associated with more favorable prognostic markers of subclinical atherosclerosis and cardiac autonomic function.
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Affiliation(s)
- Aikaterini Barmpagianni
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece.
| | - Georgios Karamanakos
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece
| | - Ioanna A Anastasiou
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece
| | - Aikaterini Kountouri
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece
| | - Vaia Lambadiari
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece
| | - Stavros Liatis
- National and Kapodistrian University of Athens First Department of Propaedeutic and Internal Medicine, Laiko General Hospital Athens, Attiki, Greece
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Accacha S, Voloshyna I, Kasselman LJ, Mejia-Corletto J, Srivastava A, Renna HA, De Leon J, Levine RL, Reiss AB. Plasma from type 1 diabetes patients promotes pro-atherogenic cholesterol transport in human macrophages. J Investig Med 2025; 73:183-192. [PMID: 39417428 DOI: 10.1177/10815589241296025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits RCT by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HCs) and 20 patients with type 1 diabetes mellitus (T1DM), 10-19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, and 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, and CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of N-(carboxymethyl)-lysine-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized low-density lipoprotein. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.
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Affiliation(s)
- Siham Accacha
- Department of Pediatrics, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Iryna Voloshyna
- Department of Medicine, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Lora J Kasselman
- Hackensack Meridian Jersey Shore University Medical Center, Hackensack, NJ, USA
| | | | - Ankita Srivastava
- Department of Medicine, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Heather A Renna
- Department of Medicine, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Joshua De Leon
- Department of Medicine, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Robert L Levine
- Department of Pediatrics, NYU Langone Hospital Long Island, Mineola, NY, USA
| | - Allison B Reiss
- Department of Medicine, NYU Langone Hospital Long Island, Mineola, NY, USA
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Ozde S, Yavuzyilmaz F, Ozel MA, Kayapinar O, Ozde C, Akture G, Arslanoglu I. Evaluation of Serum Soluble Lectin-like Oxidised Low-Density Lipoprotein Receptor-1 (sLOX-1) Level in Children with Non-Complicated Type-1 Diabetes Mellitus (T1DM) and Its Relationship with Carotid Intima Media Thickness (cIMT). J Clin Med 2025; 14:935. [PMID: 39941605 PMCID: PMC11818572 DOI: 10.3390/jcm14030935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 01/10/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Background: The objective of this study was to evaluate serum soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) levels in children with type-1 diabetes mellitus (T1DM) without any atherosclerotic complications and to investigate whether there was an association with early atherosclerotic processes in these children. Methods: The study's design entailed a prospective cross-sectional observational study methodology. The patient group consisted of 80 consecutive children aged 8-18 years who had been diagnosed with T1DM for at least ten years and had not developed any chronic clinical complications related to T1DM. The control group consisted of 72 completely healthy children with similar demographic characteristics. Serum levels of sLOX-1 were measured, and carotid intima-media thickness (cIMT) was evaluated using ultrasonography in all subjects. Results: A statistical analysis of the results was conducted. The serum sLOX-1 level was found to be significantly higher in the patient group than in the control group (0.49 ± 0.11 vs. 0.82 ± 0.35; p < 0.001). The statistical significance observed was maintained in the multivariable logistic regression analysis (p < 0.001). A significant correlation was identified between cIMT and serum sLOX-1 levels (r = 0.669, p < 0.001). The receiver operating characteristic curve for sLOX-1 indicated that a cutoff value greater than 0.65 ng/mL was associated with T1DM. Conclusions: Serum sLOX-1 levels were markedly elevated in children with T1DM who had not yet manifested chronic complications. These findings suggest that elevated serum sLOX-1 levels may be associated with the progression of atherosclerosis in children with T1DM.
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Affiliation(s)
- Sukriye Ozde
- Department of General Pediatric, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey;
| | - Fatma Yavuzyilmaz
- Department of Pediatric Endocrinology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; (F.Y.); (I.A.)
| | - Mehmet Ali Ozel
- Department of Radiology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey;
| | - Osman Kayapinar
- Department of Cardiology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; (C.O.); (G.A.)
| | - Cem Ozde
- Department of Cardiology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; (C.O.); (G.A.)
| | - Gulsah Akture
- Department of Cardiology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; (C.O.); (G.A.)
| | - Ilknur Arslanoglu
- Department of Pediatric Endocrinology, Faculty of Medicine, Duzce University, 81620 Duzce, Turkey; (F.Y.); (I.A.)
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Shriya ASK, Pawar VB, Paul AA. Diabetic Heart Disease: An Intricate Interplay of a Widespread Metabolic Disorder with the Cardiovascular System. Curr Diabetes Rev 2025; 21:93-101. [PMID: 38994615 DOI: 10.2174/0115733998305019240702095537] [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: 02/19/2024] [Revised: 06/04/2024] [Accepted: 06/14/2024] [Indexed: 07/13/2024]
Abstract
Diabetes is a chronic medical condition that causes high glycaemic levels, leading to damage to vital organs over time. It is a common disease worldwide, affecting around 422 million individuals living in middle- and low-income countries, which make up most of the population. Unfortunately, diabetes results in 1.5 million deaths annually. Diabetic patients are at a higher risk for developing cardiovascular conditions. Diabetic heart disease constitutes multiple genres, including diabetic cardiomyopathy, coronary artery disease, and heart failure. Hypoglycaemic agents aim to prevent these metabolic issues however some of these are cardiotoxic in nature. In contrast, other hypoglycaemic agents work beyond controlling glycaemic levels with their cardioprotective properties. Given that there is an alarming increase in diabetic heart disease cases universally, we have attempted to review the existing data on the topic and the effects of hypoglycaemic drugs on heart diseases.
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Affiliation(s)
- A S Kamakshi Shriya
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570015, Karnataka, India
| | - Vaishnavi B Pawar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570015, Karnataka, India
| | - Acsah Annie Paul
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, 570015, Karnataka, India
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Saloň A, Schmid-Zalaudek K, Steuber B, Müller A, Moser O, Alnuaimi S, Fredriksen PM, Ngwenchi Nkeh-Chungag B, Goswami N. Acute effects of exercise on macro- and microvasculature in individuals with type 1 diabetes - a secondary outcome analysis. Front Endocrinol (Lausanne) 2024; 15:1406930. [PMID: 39280005 PMCID: PMC11393779 DOI: 10.3389/fendo.2024.1406930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 08/06/2024] [Indexed: 09/18/2024] Open
Abstract
Background Type 1 diabetes is a chronic autoimmune disease associated with insulin-producing beta cell destruction, declining insulin secretion, and elevated blood glucose. Physical activity improves glycaemic control and cardiovascular health. This study explores acute effects of maximal exhaustion induced by a cardiopulmonary exercise on macro- and microvascular parameters in type 1 diabetes. Methodology Twenty-five participants with type 1 diabetes (14 males, 11 females), aged 41.4 ± 11.87 years, BMI 23.7 ± 3.08, completed a repeated-measure study. Measurements pre-, post-, 30- and 60-minutes post-exhaustion involved a maximal incremental cardio-pulmonary exercise test. Macro- and microvascular parameters were assessed using VICORDER® and retinal blood vessel image analysis. Repeated measures ANOVA in SPSS (Version 27.0) analysed data. Results Post-exercise, heart rate increased (p<.001), and diastolic blood pressure decreased (p=.023). Diabetes duration correlated with pulse wave velocity (r=0.418, p=.047), diastolic blood pressure (r=0.470, p=.023), and central retinal arteriolar equivalent (r=0.492, p=.023). Conclusion In type 1 diabetes, cardiopulmonary exercise-induced exhaustion elevates heart rate and reduces diastolic blood pressure. Future research should explore extended, rigorous physical activity protocols for greater cardiovascular risk reduction.
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Affiliation(s)
- Adam Saloň
- Division of Physiology & Pathophysiology, Otto Loewi Research Centre for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, Graz, Austria
- Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Inland Norway University of Applied Sciences, Hamar, Norway
- Vascular Biology Center, Augusta University, Augusta, GA, United States
| | - Karin Schmid-Zalaudek
- Division of Physiology & Pathophysiology, Otto Loewi Research Centre for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, Graz, Austria
| | - Bianca Steuber
- Division of Physiology & Pathophysiology, Otto Loewi Research Centre for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, Graz, Austria
| | - Alexander Müller
- Trials Unit for Interdisciplinary Metabolic Medicine, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Othmar Moser
- Trials Unit for Interdisciplinary Metabolic Medicine, Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Exercise Physiology & Metabolism, Institute of Sports Science, University of Bayreuth, Bayreuth, Germany
| | - Suhaila Alnuaimi
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Per Morten Fredriksen
- Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Inland Norway University of Applied Sciences, Hamar, Norway
- Faculty of Health, Welfare and Organization, Østfold University College, Fredrikstad, Norway
| | - Benedicta Ngwenchi Nkeh-Chungag
- Department of Biological and Environmental Sciences, Faculty of Natural Sciences, Walter Sisulu University, Mthatha, South Africa
| | - Nandu Goswami
- Division of Physiology & Pathophysiology, Otto Loewi Research Centre for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, Graz, Austria
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Integrative Health Department, Alma Mater Europeae, Maribor, Slovenia
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Watso JC, Robinson AT, Singar SAB, Cuba JN, Koutnik AP. Advanced cardiovascular physiology in an individual with type 1 diabetes after 10-year ketogenic diet. Am J Physiol Cell Physiol 2024; 327:C446-C461. [PMID: 38912731 PMCID: PMC11427101 DOI: 10.1152/ajpcell.00694.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Adults with type 1 diabetes (T1D) have an elevated risk for cardiovascular disease (CVD) compared with the general population. HbA1c is the primary modifiable risk factor for CVD in T1D. Fewer than 1% of patients achieve euglycemia (<5.7% HbA1c). Ketogenic diets (KD; ≤50 g carbohydrate/day) may improve glycemia and downstream vascular dysfunction in T1D by reducing HbA1c and insulin load. However, there are concerns regarding the long-term CVD risk from a KD. Therefore, we compared data collected in a 60-day window in an adult with T1D on exogenous insulin who consumed a KD for 10 years versus normative values in those with T1D (T1D norms). The participant achieved euglycemia with an HbA1c of 5.5%, mean glucose of 98 [5] mg/dL (median [interquartile range]), 90 [11]% time-in-range 70-180 mg/dL (T1D norms: 1st percentile for all), and low insulin requirements of 0.38 ± 0.03 IU/kg/day (T1D norms: 8th percentile). Seated systolic blood pressure (SBP) was 113 mmHg (T1D norms: 18th percentile), while ambulatory awake SBP was 132 ± 15 mmHg (T1D target: <130 mmHg), blood triglycerides were 69 mg/dL (T1D norms: 34th percentile), low-density lipoprotein was 129 mg/dL (T1D norms: 60th percentile), heart rate was 56 beats/min (T1D norms: >1SD below the mean), carotid-femoral pulse wave velocity was 7.17 m/s (T1D norms: lowest quartile of risk), flow-mediated dilation was 12.8% (T1D norms: >1SD above mean), and cardiac vagal baroreflex gain was 23.5 ms/mmHg (T1D norms: >1SD above mean). Finally, there was no indication of left ventricular diastolic dysfunction from echocardiography. Overall, these data demonstrate below-average CVD risk relative to T1D norms despite concerns regarding the long-term impact of a KD on CVD risk.NEW & NOTEWORTHY Adults with type 1 diabetes (T1D) have a 10-fold higher risk for cardiovascular disease (CVD) compared with the general population. We assessed cardiovascular health metrics in an adult with T1D who presented with a euglycemic HbA1c after following a ketogenic diet for the past 10 years. Despite concerns about the ketogenic diet increasing CVD risk, the participant exhibited below-average CVD risk relative to others with T1D when considering all outcomes together.
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Affiliation(s)
- Joseph C Watso
- Cardiovascular and Applied Physiology Laboratory, Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, Florida, United States
| | - Austin T Robinson
- Neurovascular Physiology Laboratory, Indiana University, Bloomington, Indiana, United States
| | - Saiful Anuar Bin Singar
- Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, Florida, United States
| | - Jens N Cuba
- Cardiovascular and Applied Physiology Laboratory, Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, Florida, United States
| | - Andrew P Koutnik
- Sansum Diabetes Research Institute, Santa Barbara, California, United States
- Human Healthspan, Resilience, and Performance, Florida Institute for Human and Machine Cognition, Pensacola, Florida, United States
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Ozde S, Akture G, Ozel MA, Yavuzyilmaz F, Arslanoglu I, Ozde C, Kayapinar O, Coskun G. Evaluation of the systemic-immune inflammation index (SII) and systemic immune-inflammation response index (SIRI) in children with type 1 diabetes mellitus and its relationship with cumulative glycemic exposure. J Pediatr Endocrinol Metab 2024; 37:635-643. [PMID: 38826052 DOI: 10.1515/jpem-2024-0043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 05/11/2024] [Indexed: 06/04/2024]
Abstract
OBJECTIVES In this study, the systemic proinflammatory status was assessed using the systemic immune-inflammation index (SII) and SIRI systemic immune-inflammatory response index (SIRI) in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS The study involved 159 patients aged between 6 and 16 years. The SII and SIRI values were calculated based on the complete blood count. Basic blood biochemistry evaluated, and carotid intima-media thickness (cIMT) was measured and recorded. The cumulative glycemic exposure was calculated by multiplying the value above the normal reference range of the HbA1c value. The sum of all these values obtained from the time of diagnosis to obtain the cumulative glycemic exposure. All findings were compared statistically. All statistically significant parameters were evaluated in the multivariate logistic regression analysis. RESULTS The analysis revealed that only cIMT (Exp(B)/OR: 0.769, 95 % CI: 0.694-0.853, p<0.001), high-density lipoprotein (Exp(B)/OR: 3.924, 95 % CI: 2.335-6.596, p<0.001), monocyte count (Exp(B)/OR: 1.650, 95 % CI: 1.257-2.178, p<0.001), hematocrit (Exp(B)/OR: 0.675, 95 % CI: 0.523-0.870, p<0.001), and SIRI (Exp(B)/OR: 1.005, 95 % CI: 1.002-1.008, p<0.001) were significantly associated with T1DM. A statistically significant positive association was found between cumulative glycemic exposure and SIRI only (r=0.213, p=0.032). To our knowledge, this is the first study to evaluate SII and SIRI in children with type 1 diabetes. CONCLUSIONS These findings indicate that SIRI could serve as a potential biomarker for detecting early-onset proatherosclerotic processes in diabetic children. However, further clinical studies are required to confirm this.
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Affiliation(s)
- Sukriye Ozde
- Department of General Pediatric, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Gulsah Akture
- Department of Cardiology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Mehmet Ali Ozel
- Department of Radiology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Fatma Yavuzyilmaz
- Department of Radiology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Ilknur Arslanoglu
- Department of Pediatric Endocrinology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Cem Ozde
- Department of Cardiology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Osman Kayapinar
- Department of Cardiology, Duzce University Faculty of Medicine, Duzce, Türkiye
| | - Gokhan Coskun
- Department of Cardiology, Duzce University Faculty of Medicine, Duzce, Türkiye
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Hajaj H, Elouali A, Ghanam A, Rkain M, Babakhouya A. Acute Myocardial Infarction in a Seven-Year-Old Child With Type 1 Diabetes: A Rare Case Report. Cureus 2024; 16:e62909. [PMID: 39040722 PMCID: PMC11262754 DOI: 10.7759/cureus.62909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2024] [Indexed: 07/24/2024] Open
Abstract
Myocardial infarction (MI) is extremely rare in children and can have different etiologies, including congenital heart defects and Kawasaki disease. Cardiovascular disease (CVD) is the primary cause of death in patients with type 1 diabetes (T1D). Effective management of risk factors like blood pressure, cholesterol, and blood sugar levels is essential for individuals with T1D to mitigate the risk of cardiovascular complications, including MI. We present the case of a seven-year-old child diagnosed with type 1 diabetes one month before this admission, without any other notable medical history, who was admitted to the pediatric emergency department due to chest pain. The symptoms had begun two hours prior to admission. Upon arrival, the patient reported severe and persistent retrosternal constrictive chest pain radiating to the left arm without other associated signs, with a strictly normal clinical examination. An electrocardiogram (ECG) revealed typical ST segment elevation in inferior leads (II, III, and aVF) with reciprocal changes in V1 to V4. Troponin level was elevated at 7254 ng/l. Echocardiography revealed mild dilation of the left coronary artery (4 mm) and the right coronary artery (3 mm), while other radiological and laboratory investigations showed no abnormalities. The patient responded well to treatment with acetylsalicylic acid, clopidogrel, and heparin, resulting in a favorable outcome.
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Affiliation(s)
- Hanane Hajaj
- Faculty of Medicine and Pharmacy, Mother and Child Health Laboratory, Mohammed First University, Oujda, MAR
- Department of Pediatrics, Mohammed VI University Hospital, Oujda, MAR
| | - Aziza Elouali
- Faculty of Medicine and Pharmacy, Mother and Child Health Laboratory, Mohammed First University, Oujda, MAR
- Department of Pediatrics, Mohammed VI University Hospital, Oujda, MAR
| | - Ayad Ghanam
- Faculty of Medicine and Pharmacy, Mother and Child Health Laboratory, Mohammed First University, Oujda, MAR
- Department of Pediatrics, Mohammed VI University Hospital, Oujda, MAR
| | - Maria Rkain
- Faculty of Medicine and Pharmacy, Mother and Child Health Laboratory, Mohammed First University, Oujda, MAR
- Department of Pediatrics, Mohammed VI University Hospital, Oujda, MAR
| | - Abdeladim Babakhouya
- Faculty of Medicine and Pharmacy, Mother and Child Health Laboratory, Mohammed First University, Oujda, MAR
- Department of Pediatrics, Mohammed VI University Hospital, Oujda, MAR
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Yi M, Toribio AJ, Salem YM, Alexander M, Ferrey A, Swentek L, Tantisattamo E, Ichii H. Nrf2 Signaling Pathway as a Key to Treatment for Diabetic Dyslipidemia and Atherosclerosis. Int J Mol Sci 2024; 25:5831. [PMID: 38892018 PMCID: PMC11172493 DOI: 10.3390/ijms25115831] [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: 04/01/2024] [Revised: 05/13/2024] [Accepted: 05/18/2024] [Indexed: 06/21/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic endocrine disorder that affects more than 20 million people in the United States. DM-related complications affect multiple organ systems and are a significant cause of morbidity and mortality among people with DM. Of the numerous acute and chronic complications, atherosclerosis due to diabetic dyslipidemia is a condition that can lead to many life-threatening diseases, such as stroke, coronary artery disease, and myocardial infarction. The nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway is an emerging antioxidative pathway and a promising target for the treatment of DM and its complications. This review aims to explore the Nrf2 pathway's role in combating diabetic dyslipidemia. We will explore risk factors for diabetic dyslipidemia at a cellular level and aim to elucidate how the Nrf2 pathway becomes a potential therapeutic target for DM-related atherosclerosis.
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Affiliation(s)
- Michelle Yi
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
| | - Arvin John Toribio
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
| | - Yusuf Muhammad Salem
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
| | - Michael Alexander
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
| | - Antoney Ferrey
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA; (A.F.); (E.T.)
| | - Lourdes Swentek
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
| | - Ekamol Tantisattamo
- Department of Medicine, University of California Irvine, Irvine, CA 92697, USA; (A.F.); (E.T.)
| | - Hirohito Ichii
- Department of Surgery, University of California Irvine, Irvine, CA 92697, USA; (M.Y.); (A.J.T.); (Y.M.S.); (M.A.); (L.S.)
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Yu J, Liu H, Chen Y, Wang L, Chen P, Zhao Y, Ou C, Chen W, Hu J, Wang Y, Wang Y. miR-449a disturbs atherosclerotic plaque stability in streptozotocin and high-fat diet-induced diabetic mice by targeting CEACAM1. Diabetol Metab Syndr 2024; 16:98. [PMID: 38715117 PMCID: PMC11077876 DOI: 10.1186/s13098-024-01322-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 03/28/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND Emerging evidence indicates carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is involved in the development of atherosclerosis (AS). However, the roles and functions of CEACAM1 in AS remain unknown. Therefore, this study aims to investigate the roles and molecular functions of CEACAM1 in AS. METHODS We constructed a diabetes mellitus (DM) + high-fat diet (HFD) mouse model based on the streptozotocin (STZ)-induced apolipoprotein E-knockdown (ApopE-/-) mouse to investigate the roles and regulatory mechanism of miR-449a/CEACAM1 axis. The mRNA expression and protein levels in this study were examined using quantity PCR, western blot, immunofluorescence (IF), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC), respectively. And the lipid deposition and collagen content were detected using Oil Red O and Sirius Red staining. Cell apoptosis, migration, invasion, and tuber formation were detected by Annexin-V FITC/PI, wound healing, transwell, and tuber formation assays, respectively. The relationship between miR-449a and CEACAM1 was determined by a dual-luciferase reporter gene assay. RESULTS miR-449a and MMP-9 were upregulated, and CEACAM1 was downregulated in the DM + HFD MOUSE model. Upregulation of CEACAM1 promoted atherosclerotic plaque stability and inhibited inflammation in the DM + HFD mouse model. And miR-449a directly targeted CEACAM1. Besides, miR-449a interacted with CEACAM1 to regulate atherosclerotic plaque stability and inflammation in DM-associated AS mice. In vitro, the rescue experiments showed miR-449a interacted with CEACAM1 to affect apoptosis, migration, invasion, and tuber formation ability in high glucose (HG)-induced HUVECs. CONCLUSION These results demonstrated that miR-449a promoted plaque instability and inflammation in DM and HFD-induced mice by targeting CEACAM1.
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Affiliation(s)
- Jie Yu
- Department of Thoracocardiac Surgery, 920th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, No.212 Daguan Rd, Kunming, Yunnan, 650032, China
| | - Han Liu
- Department of Emergency Medicine, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Yu Chen
- Department of Cardiology, 920th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, No.212 Daguan Rd, Kunming, Yunnan, 650032, China
| | - Ling Wang
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Peng Chen
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Yue Zhao
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Chunxia Ou
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Wei Chen
- Department of Radiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Jie Hu
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China
| | - Yu Wang
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China.
| | - Yan Wang
- Laboratory of Molecular Cardiology, Department of Cardiology, The First Affiliated Hospital of Kunming Medical University, No.295 Xichang Rd, Kunming, Yunnan, 650032, China.
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Lai SWT, Hernandez-Castillo C, Gonzalez EDJL, Zoukari T, Talley M, Paquin N, Chen Z, Roep BO, Kaddis JS, Natarajan R, Termini J, Shuck SC. Methylglyoxal Adducts Are Prognostic Biomarkers for Diabetic Kidney Disease in Patients With Type 1 Diabetes. Diabetes 2024; 73:611-617. [PMID: 37967313 PMCID: PMC10958582 DOI: 10.2337/db23-0277] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 11/06/2023] [Indexed: 11/17/2023]
Abstract
More than 30% of patients with type 1 diabetes develop diabetic kidney disease (DKD), which significantly increases mortality risk. The Diabetes Control and Complications Trial (DCCT) and follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC), established that glycemic control measured by HbA1c predicts DKD risk. However, the continued high incidence of DKD reinforces the urgent need for additional biomarkers to supplement HbA1c. Here, we assessed biomarkers induced by methylglyoxal (MG), a metabolic by-product that forms covalent adducts on DNA, RNA, and proteins, called MG adducts. Urinary MG adducts were measured in samples from patients with type 1 diabetes enrolled in DCCT/EDIC who did (case patients; n = 90) or did not (control patients; n = 117) develop DKD. Univariate and multivariable analyses revealed that measurements of MG adducts independently predict DKD before established DKD biomarkers such as glomerular filtration rate and albumin excretion rate. Elevated levels of MG adducts bestowed the greatest risk of developing DKD in a multivariable model that included HbA1c and other clinical covariates. Our work establishes a novel class of biomarkers to predict DKD risk and suggests that inclusion of MG adducts may be a valuable tool to improve existing predictors of complications like DKD prior to overt disease, and to aid in identifying at-risk individuals and personalized risk management. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Carlos Hernandez-Castillo
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Tala Zoukari
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Min Talley
- Biostatistics and Mathematical Oncology Core, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Nadia Paquin
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Bart O. Roep
- Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - John S. Kaddis
- Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - John Termini
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
| | - Sarah C. Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
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Kal S, Mahata S, Jati S, Mahata SK. Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives. Peptides 2024; 172:171147. [PMID: 38160808 PMCID: PMC10838678 DOI: 10.1016/j.peptides.2023.171147] [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: 11/28/2023] [Revised: 12/27/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimer's disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.
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Affiliation(s)
- Satadeepa Kal
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Sumana Mahata
- Department of Anesthesiology, Riverside University Health System, Moreno Valley, CA, USA
| | - Suborno Jati
- Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA
| | - Sushil K Mahata
- Department of Medicine, University of California San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, San Diego, CA, USA.
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13
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Yu D, Cai Y, Osuagwu UL, Pickering K, Baker J, Cutfield R, Orr-Walker BJ, Sundborn G, Wang Z, Zhao Z, Simmons D. All-cause, premature, and cardiovascular death attributable to socioeconomic and ethnic disparities among New Zealanders with type 1 diabetes 1994-2019: a multi-linked population-based cohort study. BMC Public Health 2024; 24:298. [PMID: 38273238 PMCID: PMC10811898 DOI: 10.1186/s12889-023-17326-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Accepted: 11/24/2023] [Indexed: 01/27/2024] Open
Abstract
BACKGROUND New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ). METHODS The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities. RESULTS Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively. CONCLUSIONS Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.
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Affiliation(s)
- Dahai Yu
- Department of Nephrology, the First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, China
- Primary Care Centre Versus Arthritis, School of Medicine, Keele University, Keele, ST5 5BG, UK
| | - Yamei Cai
- Department of Nephrology, the First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, China
| | - Uchechukwu Levi Osuagwu
- School of Medicine, Western Sydney University, Locked Bag 1797, Campbelltown, NSW 2751, Australia
| | | | - John Baker
- Diabetes Foundation Aotearoa, Otara, New Zealand
- Department of Diabetes and Endocrinology, Counties Manukau Health, Auckland, New Zealand
| | - Richard Cutfield
- Diabetes Foundation Aotearoa, Otara, New Zealand
- Department of Diabetes and Endocrinology, Waitemata District Health Board, Auckland, New Zealand
| | - Brandon J Orr-Walker
- Diabetes Foundation Aotearoa, Otara, New Zealand
- Department of Diabetes and Endocrinology, Counties Manukau Health, Auckland, New Zealand
| | - Gerhard Sundborn
- Section of Pacific Health, the University of Auckland, Auckland, New Zealand
| | - Zheng Wang
- Department of Nephrology, the First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, China
| | - Zhanzheng Zhao
- Department of Nephrology, the First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, China.
| | - David Simmons
- Department of Nephrology, the First Affiliated Hospital Zhengzhou University, Zhengzhou, 450052, China.
- School of Medicine, Western Sydney University, Locked Bag 1797, Campbelltown, NSW 2751, Australia.
- Diabetes Foundation Aotearoa, Otara, New Zealand.
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Lai SWT, Bhattacharya S, Lopez Gonzalez EDJ, Shuck SC. Methylglyoxal-Derived Nucleoside Adducts Drive Vascular Dysfunction in a RAGE-Dependent Manner. Antioxidants (Basel) 2024; 13:85. [PMID: 38247509 PMCID: PMC10812505 DOI: 10.3390/antiox13010085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/23/2024] Open
Abstract
Diabetic kidney disease (DKD) is a leading cause of death in patients with diabetes. An early precursor to DKD is endothelial cell dysfunction (ECD), which often precedes and exacerbates vascular disease progression. We previously discovered that covalent adducts formed on DNA, RNA, and proteins by the reactive metabolic by-product methylglyoxal (MG) predict DKD risk in patients with type 1 diabetes up to 16 years pre-diagnosis. However, the mechanisms by which MG adducts contribute to vascular disease onset and progression remain unclear. Here, we report that the most predominant MG-induced nucleoside adducts, N2-(1-carboxyethyl)-deoxyguanosine (CEdG) and N2-(1-carboxyethyl)-guanosine (CEG), drive endothelial dysfunction. Following CEdG or CEG exposure, primary human umbilical vein endothelial cells (HUVECs) undergo endothelial dysfunction, resulting in enhanced monocyte adhesion, increased reactive oxygen species production, endothelial permeability, impaired endothelial homeostasis, and exhibit a dysfunctional transcriptomic signature. These effects were discovered to be mediated through the receptor for advanced glycation end products (RAGE), as an inhibitor for intracellular RAGE signaling diminished these dysfunctional phenotypes. Therefore, we found that not only are MG adducts biomarkers for DKD, but that they may also have a role as potential drivers of vascular disease onset and progression and a new therapeutic modality.
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Affiliation(s)
- Seigmund Wai Tsuen Lai
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
| | - Supriyo Bhattacharya
- Department of Computational and Quantitative Medicine, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA;
| | - Edwin De Jesus Lopez Gonzalez
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
| | - Sarah C. Shuck
- Department of Diabetes and Cancer Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; (S.W.T.L.); (E.D.J.L.G.)
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15
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Beatty C, Richardson KP, Tran PMH, Satter KB, Hopkins D, Gardiner M, Sharma A, Purohit S. Multiplex analysis of inflammatory proteins associated with risk of coronary artery disease in type-1 diabetes patients. Clin Cardiol 2024; 47:e24143. [PMID: 37822049 PMCID: PMC10768730 DOI: 10.1002/clc.24143] [Citation(s) in RCA: 1] [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: 07/18/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 10/13/2023] Open
Abstract
BACKGROUND Chronic uncontrolled hyperglycemia, a precursor to chronic low-grade inflammation, is a leading cause of coronary artery disease (CAD) due to plaque buildup in type-1 diabetes (T1D) patients. We evaluated levels of 22 inflammatory markers in cross-sectional serum samples from 1222 subjects to evaluate their potential as risk factors for CAD in T1D patients. HYPOTHESIS Circulating levels of markers of inflammation may be the risk factors for incident CAD. METHODS The T1D subjects were divided into two groups: those without CAD (n = 1107) and with CAD (n = 115). Serum levels of proteins were assayed using multiplex immunoassays on a Luminex Platform. Differences between the two groups were made by univariate analysis. Multivariate logistic regression was used to ascertain the potential of proteins as risk factors for CAD. Influence of age, duration of diabetes, sex, hypertension, and dyslipidemia was determined in a stepwise manner. Serum levels of 22 proteins were combined into a composite score using Ridge regression for risk-based stratification. RESULTS Mean levels of CRP, IGFBP1, IGFBP2, insulin-like growth factors binding protein-6 (IGFBP6), MMP1, SAA, sTNFRI, and sTNFRII were elevated in CAD patients (n = 115) compared to T1D patients without CAD (nCAD, n = 1107). After adjusting for age, duration of diabetes, sex, hypertension, and dyslipidemia, higher levels of sTNFRI (odds ratio [OR] = 2.18, 1.1 × 10-3 ), sTNFRII (OR = 1.52, 1 × 10-2 ), and IGFBP6 (OR = 3.62, 1.8 × 10-3 ) were significantly associated with CAD. The composite score based on Ridge regression, was able to stratify CAD patients into low, medium, and high-risk groups. CONCLUSIONS The results show activation of the TNF pathway in CAD patients. Evaluating these markers in serum can be a potential tool for identifying high-risk T1D patients for intensive anti-inflammatory therapeutic interventions.
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Affiliation(s)
- Carol Beatty
- School of MedicineMedical College of GeorgiaAugustaGeorgiaUSA
| | - Katherine P. Richardson
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
| | - Paul M. H. Tran
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
- Department of Internal MedicineYale School of MedicineNew HavenConnecticutUSA
| | - Khaled B. Satter
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
- Department of PathologyNational Institutes of HealthBethesdaMarylandUSA
| | - Diane Hopkins
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
| | - Melissa Gardiner
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
| | - Ashok Sharma
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
| | - Sharad Purohit
- School of MedicineCenter for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
- Department of Obstetrics and GynecologyMedical College of Georgia, Augusta UniversityAugustaGeorgiaUSA
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Rybarczyk A, Formanowicz D, Formanowicz P. Key Therapeutic Targets to Treat Hyperglycemia-Induced Atherosclerosis Analyzed Using a Petri Net-Based Model. Metabolites 2023; 13:1191. [PMID: 38132873 PMCID: PMC10744714 DOI: 10.3390/metabo13121191] [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: 11/10/2023] [Revised: 11/29/2023] [Accepted: 12/05/2023] [Indexed: 12/23/2023] Open
Abstract
Chronic superphysiological glucose concentration is a hallmark of diabetes mellitus (DM) and a cause of damage to many types of cells. Atherosclerosis coexists with glucose metabolism disturbances, constituting a significant problem and exacerbating its complications. Atherosclerosis in DM is accelerated, so it is vital to slow its progression. However, from the complex network of interdependencies, molecules, and processes involved, choosing which ones should be inhibited without blocking the pathways crucial for the organism's functioning is challenging. To conduct this type of analysis, in silicotesting comes in handy. In our study, to identify sites in the network that need to be blocked to have an inhibitory effect on atherosclerosis in hyperglycemia, which is toxic for the human organism, we created a model using Petri net theory and performed analyses. We have found that blocking isoforms of protein kinase C (PKC)-PKCβ and PKCγ-in diabetic patients can contribute to the inhibition of atherosclerosis progression. In addition, we have discovered that aldose reductase inhibition can slow down atherosclerosis progression, and this has been shown to reduce PKC (β and γ) expression in DM. It has also been observed that diminishing oxidative stress through the inhibitory effect on the AGE-RAGE axis may be a promising therapeutic approach in treating hyperglycemia-induced atherosclerosis. Moreover, the blockade of NADPH oxidase, the key enzyme responsible for the formation of reactive oxygen species (ROS) in blood vessels, only moderately slowed down atherosclerosis development. However, unlike aldose reductase blockade, or direct PKC (β and γ), the increased production of mitochondrial ROS associated with mitochondrial dysfunction effectively stopped after NADPH oxidase blockade. The results obtained may constitute the basis for further in-depth research.
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Affiliation(s)
- Agnieszka Rybarczyk
- Institute of Computing Science, Poznan University of Technology, 60-695 Poznan, Poland;
- Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland
- Faculty of Electrical Engineering, Gdynia Maritime University, 81-225 Gdynia, Poland
| | - Dorota Formanowicz
- Department of Medical Chemistry and Laboratory Medicine, Poznan University of Medical Sciences, 60-806 Poznan, Poland;
| | - Piotr Formanowicz
- Institute of Computing Science, Poznan University of Technology, 60-695 Poznan, Poland;
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17
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Varkevisser RDM, Mul D, Aanstoot HJ, Wolffenbuttel BHR, van der Klauw MM. Differences in lipid and blood pressure measurements between individuals with type 1 diabetes and the general population: a cross-sectional study. BMJ Open 2023; 13:e073690. [PMID: 37880169 PMCID: PMC10603478 DOI: 10.1136/bmjopen-2023-073690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 09/18/2023] [Indexed: 10/27/2023] Open
Abstract
OBJECTIVES Cardiovascular disease (CVD) is a precarious complication of type 1 diabetes (T1D). Alongside glycaemic control, lipid and blood pressure (BP) management are essential for the prevention of CVD. However, age-specific differences in lipid and BP between individuals with T1D and the general population are relatively unknown. DESIGN Cross-sectional study. SETTING Six diabetes outpatient clinics and individuals from the Lifelines cohort, a multigenerational cohort from the Northern Netherlands. PARTICIPANTS 2178 adults with T1D and 146 22 individuals without diabetes from the general population. PRIMARY AND SECONDARY OUTCOME MEASURES Total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol), systolic BP (SBP) and diastolic BP (DBP), stratified by age group, glycated haemoglobin category, medication use and sex. RESULTS In total, 2178 individuals with T1D and 146 822 without diabetes were included in this study. Total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in individuals with T1D in comparison to the background population. When stratified by age and medication use, total cholesterol and LDL-cholesterol were lower and SBP and DBP were higher in the T1D population. Men with T1D achieved lower LDL-cholesterol levels both with and without medication in older age groups in comparison to women. Women with T1D had up to 8 mm Hg higher SBP compared with the background population, this difference was not present in men. CONCLUSIONS Lipid and BP measurements are not comparable between individuals with T1D and the general population and are particularly unfavourable for BP in the T1D group. There are potential sex differences in the management of LDL-cholesterol and BP.
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Affiliation(s)
| | - Dick Mul
- Center for Focussed Diabetes Care and Research, Diabeter, Rotterdam, The Netherlands
| | - Henk-Jan Aanstoot
- Center for Focussed Diabetes Care and Research, Diabeter, Rotterdam, The Netherlands
| | - Bruce H R Wolffenbuttel
- Department of Endocrinology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Melanie M van der Klauw
- Department of Endocrinology, University Medical Centre Groningen, Groningen, The Netherlands
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18
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Thielemans R, Speeckaert R, Delrue C, De Bruyne S, Oyaert M, Speeckaert MM. Unveiling the Hidden Power of Uromodulin: A Promising Potential Biomarker for Kidney Diseases. Diagnostics (Basel) 2023; 13:3077. [PMID: 37835820 PMCID: PMC10572911 DOI: 10.3390/diagnostics13193077] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/25/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023] Open
Abstract
Uromodulin, also known as Tamm-Horsfall protein, represents the predominant urinary protein in healthy individuals. Over the years, studies have revealed compelling associations between urinary and serum concentrations of uromodulin and various parameters, encompassing kidney function, graft survival, cardiovascular disease, glucose metabolism, and overall mortality. Consequently, there has been a growing interest in uromodulin as a novel and effective biomarker with potential applications in diverse clinical settings. Reduced urinary uromodulin levels have been linked to an elevated risk of acute kidney injury (AKI) following cardiac surgery. In the context of chronic kidney disease (CKD) of different etiologies, urinary uromodulin levels tend to decrease significantly and are strongly correlated with variations in estimated glomerular filtration rate. The presence of uromodulin in the serum, attributable to basolateral epithelial cell leakage in the thick ascending limb, has been observed. This serum uromodulin level is closely associated with kidney function and histological severity, suggesting its potential as a biomarker capable of reflecting disease severity across a spectrum of kidney disorders. The UMOD gene has emerged as a prominent locus linked to kidney function parameters and CKD risk within the general population. Extensive research in multiple disciplines has underscored the biological significance of the top UMOD gene variants, which have also been associated with hypertension and kidney stones, thus highlighting the diverse and significant impact of uromodulin on kidney-related conditions. UMOD gene mutations are implicated in uromodulin-associated kidney disease, while polymorphisms in the UMOD gene show a significant association with CKD. In conclusion, uromodulin holds great promise as an informative biomarker, providing valuable insights into kidney function and disease progression in various clinical scenarios. The identification of UMOD gene variants further strengthens its relevance as a potential target for better understanding kidney-related pathologies and devising novel therapeutic strategies. Future investigations into the roles of uromodulin and regulatory mechanisms are likely to yield even more profound implications for kidney disease diagnosis, risk assessment, and management.
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Affiliation(s)
- Raïsa Thielemans
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
| | | | - Charlotte Delrue
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
| | - Sander De Bruyne
- Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; (S.D.B.); (M.O.)
| | - Matthijs Oyaert
- Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium; (S.D.B.); (M.O.)
| | - Marijn M. Speeckaert
- Department of Nephrology, Ghent University Hospital, 9000 Ghent, Belgium; (R.T.); (C.D.)
- Research Foundation Flanders, 1000 Brussels, Belgium
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19
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Sethupathi P, Matetić A, Bang V, Myint PK, Rendon I, Bagur R, Diaz-Arocutipa C, Ricalde A, Bharadwaj A, Mamas MA. Association of Diabetes Mellitus and Its Types with In-Hospital Management and Outcomes of Patients with Acute Myocardial Infarction. CARDIOVASCULAR REVASCULARIZATION MEDICINE 2023; 52:16-22. [PMID: 36854639 DOI: 10.1016/j.carrev.2023.02.008] [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: 11/13/2022] [Revised: 02/01/2023] [Accepted: 02/10/2023] [Indexed: 03/01/2023]
Abstract
BACKGROUND Diabetes mellitus (DM) is an important risk factor for adverse outcomes following acute myocardial infarction (AMI), but large-scale studies investigating the differential impact of Type 1 DM (T1DM) and Type 2 DM (T2DM) on AMI outcomes are lacking. METHODS All adult discharges for AMI in the National Inpatient Sample (October 2015 to December 2018) were included and stratified into T1DM, T2DM and non-DM (NDM) groups. Outcomes of interests were all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE), major bleeding and acute ischemic stroke, as well as invasive management. Binomial hierarchical multilevel multivariable logistic regression with adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) was used to investigate the association between DM and its subtypes with the AMI outcomes. RESULTS Out of 2,587,615 patients, there were 29,250 (1.1 %) T1DM and 1,032,925 (39.9 %) T2DM patients. After multivariable adjustment, patients with T1DM had increased odds of MACCE (aOR 1.20, 95 % CI 1.09-1.31), all-cause mortality (aOR 1.20, 95 % CI 1.08-1.33) and major bleeding (aOR 1.28, 95 % CI 1.13-1.44), whilst T2DM patients had increased odds of MACCE (aOR 1.03, 95 % CI 1.01-1.05) and ischemic stroke (aOR 1.09, 95 % CI 1.05-1.13), compared to NDM patients. The adjusted odds of receiving percutaneous coronary intervention were lower in both T1DM and T2DM patients (aOR 0.70, 95 % CI 0.66-0.75 and aOR 0.95, 95 % CI 0.94-0.96, respectively), but T2DM patients showed higher utilization of composite percutaneous and surgical revascularization (aOR 1.03, 95 % CI 1.03-1.04) compared to NDM patients. CONCLUSIONS DM patients presenting with AMI have worse in-hospital clinical outcomes compared to NDM patients. There are important DM type-related differences with T1DM patients having overall worse outcomes and receiving less overall revascularization.
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Affiliation(s)
- Priyanka Sethupathi
- Department of Cardiology, Royal Stoke Hospital, Stoke on Trent, United Kingdom
| | - Andrija Matetić
- Department of Cardiology, University Hospital of Split, Split, Croatia; Keele Cardiovascular Research Group, Centre for Prognosis Research, Keele University, United Kingdom
| | - Vijay Bang
- Lilavati Hospital and Research Center, Mumbai, India
| | - Phyo K Myint
- Aberdeen Cardiovascular & Diabetes Centre, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
| | - Ivan Rendon
- Department of Cardiology, Clinica el Rosario, ESE HMUA, Medellín, Colombia
| | - Rodrigo Bagur
- Department of Cardiology, London Health Sciences Centre, Western University, London, Ontario, Canada
| | | | - Alejandro Ricalde
- Department of Interventional Cardiology, American British Cowdray Medical Center, Mexico City, Mexico
| | - Aditya Bharadwaj
- Division of Cardiology, Loma Linda University, California, United States
| | - Mamas A Mamas
- Keele Cardiovascular Research Group, Centre for Prognosis Research, Keele University, United Kingdom.
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20
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Richardson LA, Basu A, Chien LC, Alman AC, Snell-Bergeon JK. Longitudinal Associations of Healthy Dietary Pattern Scores with Coronary Artery Calcification and Pericardial Adiposity in United States Adults with and without Type 1 Diabetes. J Nutr 2023; 153:2085-2093. [PMID: 37187353 PMCID: PMC10375506 DOI: 10.1016/j.tjnut.2023.05.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/04/2023] [Accepted: 05/11/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Pericardial adipose tissue volume (PAT) and coronary artery calcification (CAC) are prognostic indicators for future cardiovascular events; however, no studies have assessed the long-term associations of adherence to dietary patterns (DPs) with PAT and CAC in adults with and without type 1 diabetes (T1D). OBJECTIVES We investigated the longitudinal associations of the Mediterranean Diet (MedDiet) and Dietary Approaches to Stop Hypertension (DASH) diet with PAT and CAC progression in adults with and without T1D. METHODS The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study is a population-based, prospective study of 652 T1D and 764 nondiabetic mellitus (nonDM) (19-56 y) participants that began in 2000-2002 with follow-up visits in 2003-2004 and 2006-2007. At each visit, food frequency questionnaires were collected and used to develop adherence scores for the MedDiet and DASH diets. PAT and CAC were measured at each visit using electron beam computed tomography. CAC progression was defined as a ≥2.5 mm square root-transformed volume. Mixed effect models were used to conduct statistical analyses. RESULTS Combined models found a significant-0.09 cm3 (95% CI: -0.14, -0.03; P = 0.0027) inverse association in PAT for every 1-point increase in the MedDiet score and a significant-0.26 cm3 (95% CI: -0.38, -0.14; P < 0.0001) inverse association in PAT for every 1-point increase in the DASH score. In combined models, the DPs were not significantly associated with lower odds of CAC progression; however, both DPs had significant interactions by diabetes status for CAC. Only the DASH diet was associated with lower odds of CAC progression in the nonDM group (OR: 0.96; 95% CI: 0.93, 0.99; P = 0.0224). CONCLUSIONS These data suggest that the DPs are associated with lower PAT, which may reduce future cardiovascular events. The DASH diet may be beneficial for lower odds of CAC progression in those without T1D.
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Affiliation(s)
- Leigh Ann Richardson
- Department of Epidemiology and Biostatistics, University of Nevada at Las Vegas, Las Vegas, NV, United States
| | - Arpita Basu
- Department of Kinesiology and Nutrition Sciences, University of Nevada at Las Vegas, Las Vegas, NV, United States.
| | - Lung-Chang Chien
- Department of Epidemiology and Biostatistics, University of Nevada at Las Vegas, Las Vegas, NV, United States
| | - Amy C Alman
- College of Public Health, University of South Florida, Tampa, FL, United States
| | - Janet K Snell-Bergeon
- Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
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21
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Lu F, Wu B, Wang Y. Mendelian randomization indicates that atopic dermatitis contributes to the occurrence of diabetes. BMC Med Genomics 2023; 16:132. [PMID: 37322504 PMCID: PMC10268454 DOI: 10.1186/s12920-023-01575-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/08/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND An association has been indicated between atopic dermatitis (AD), a prevalent chronic inflammatory skin disease, and diabetes mellitus. However, the exact causal relationship between AD and both type 1 diabetes (T1D) and type 2 diabetes (T2D) remains controversial. This study aimed to explore the causal association between AD and diabetes by Mendelian Randomization (MR) approaches. METHODS Public genetic summary data for AD was obtained from EAGLE study. Single nucleotide polymorphisms of diabetes were retrieved from four genome-wide association studies that had been performed in European populations. Inverse variance weighted (IVW) in MR analysis was used as the primary means of causality estimation. Several complementary analyses and sensitivity analyses were performed to calculate MR estimates and to enhance the causal inference, respectively. The R package 'TwoSampleMR' was used for analysis. RESULTS Genetically predicted AD led to a higher risk of T1D (OR, 1.19; 95% CI, 1.05, 1.34; P = 0.006) and T2D (OR, 1.07; 95% CI, 1.02, 1.11; P = 0.003) based on random-effect IVW method. The complementary analyses provided similar positive results. Cochran's Q test and I2 statistics indicated moderate heterogeneity between AD and both T1D and T2D. No significant horizontal pleiotropy was detected by MR-Egger Intercept p except summary data from FinnGen consortium. CONCLUSION Genetically predicted AD is a risk factor for both T1D and T2D. These findings imply potential shared pathological mechanisms between AD and diabetes, thus suggesting the significance of early clinical diagnosis and prevention of AD in reducing the incidence of diabetes.
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Affiliation(s)
- Feiwei Lu
- Department of Echocardiography, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Boting Wu
- Department of Transfusion, Zhongshan Hospital Fudan University, Shanghai, 200032, China
| | - Yongshi Wang
- Department of Echocardiography, Zhongshan Hospital Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
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22
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Zhou Y, Liu C, Zhang Z, Chen J, Zhao D, Li L, Tong M, Zhang G. Identification and validation of diagnostic biomarkers of coronary artery disease progression in type 1 diabetes via integrated computational and bioinformatics strategies. Comput Biol Med 2023; 159:106940. [PMID: 37075605 DOI: 10.1016/j.compbiomed.2023.106940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 04/03/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023]
Abstract
OBJECTIVE Our study aimed to identify early peripheral blood diagnostic biomarkers and elucidate the immune mechanisms of coronary artery disease (CAD) progression in patients with type 1 diabetes mellitus (T1DM). METHODS Three transcriptome datasets were retrieved from the Gene Expression Omnibus (GEO) database. Gene modules associated with T1DM were selected with weighted gene co-expression network analysis. Differentially expressed genes (DEGs) between CAD and acute myocardial infarction (AMI) peripheral blood tissues were identified using limma. Candidate biomarkers were selected with functional enrichment analysis, node gene selection from a constructed protein-protein interaction (PPI) network, and 3 machine learning algorithms. Candidate expression was compared, and the receiver operating characteristic curve (ROC) and nomogram were constructed. Immune cell infiltration was assessed with the CIBERSORT algorithm. RESULTS A total of 1283 genes comprising 2 modules were detected as the most associated with T1DM. In addition, 451 DEGs related to CAD progression were identified. Among them, 182 were common to both diseases and mainly enriched in immune and inflammatory response regulation. The PPI network yielded 30 top node genes, and 6 were selected using the 3 machine learning algorithms. Upon validation, 4 genes (TLR2, CLEC4D, IL1R2, and NLRC4) were recognized as diagnostic biomarkers with the area under the curve (AUC) > 0.7. All 4 genes were positively correlated with neutrophils in patients with AMI. CONCLUSION We identified 4 peripheral blood biomarkers and provided a nomogram for early diagnosing CAD progression to AMI in patients with T1DM. The biomarkers were positively associated with neutrophils, indicating potential therapeutic targets.
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Affiliation(s)
- Yufei Zhou
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Chunjiang Liu
- Department of General Surgery, Division of Vascular Surgery, Shaoxing People's Hospital, Shaoxing, 312000, China
| | - Zhongzheng Zhang
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230000, China
| | - Jian Chen
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230000, China
| | - Di Zhao
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Linnan Li
- Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Mingyue Tong
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230000, China.
| | - Gang Zhang
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Anhui Public Health Clinical Center, Hefei, Anhui, 230000, China.
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23
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Bebu I, Braffett BH, de Boer IH, Aiello LP, Bantle JP, Lorenzi GM, Herman WH, Gubitosi-Klug RA, Perkins BA, Lachin JM, Molitch ME. Relationships Between the Cumulative Incidences of Long-term Complications in Type 1 Diabetes: The DCCT/EDIC Study. Diabetes Care 2023; 46:361-368. [PMID: 36520643 PMCID: PMC9887612 DOI: 10.2337/dc22-1744] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.
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Affiliation(s)
- Ionut Bebu
- Biostatistics Center, The George Washington University, Rockville, MD
| | | | - Ian H. de Boer
- Division of Nephrology, University of Washington, Seattle, WA
| | - Lloyd P. Aiello
- Department of Ophthalmology, Joslin Diabetes Center, Boston, MA
| | - John P. Bantle
- Department of Medicine, University of Minnesota, Minneapolis, MN
| | - Gayle M. Lorenzi
- Department of Medicine, University of California San Diego, La Jolla, CA
| | | | | | - Bruce A. Perkins
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada
| | - John M. Lachin
- Biostatistics Center, The George Washington University, Rockville, MD
| | - Mark E. Molitch
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University, Chicago, IL
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24
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Microvascular complications identify a specific coronary atherosclerotic phenotype in patients with type 2 diabetes mellitus. Cardiovasc Diabetol 2022; 21:211. [PMID: 36243750 PMCID: PMC9571474 DOI: 10.1186/s12933-022-01637-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Background Patients with type 2 diabetes mellitus (T2DM) are considered as a homogeneous cohort of patients. However, the specific role of diabetic microvascular complications (DMC), in determining the features of coronary plaques is poorly known. We investigated whether the presence of DMC may identify a different phenotype of patients associated to specific clinical, angiographic, optical coherence tomography (OCT) features and different prognosis. Methods We prospectively enrolled consecutive T2DM patients with obstructive coronary artery disease (CAD) at their first coronary event. Patients were stratified according to the presence or absence of DMC, including diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. OCT assessment of the culprit vessel was performed in a subgroup of patients. The incidence of major adverse cardiac events (MACEs) was assessed at follow-up. Results We enrolled 320 T2DM patients (mean age 70.3 ± 8.8 years; 234 [73.1%] men, 40% acute coronary syndrome, 60% chronic coronary syndrome). Patients with DMC (172 [53.75%]) presented a different clinical and biochemical profile and, of importance, a higher prevalence of multivessel CAD (109 [63.4%] vs. 68 [45.9%], p = 0.002). At OCT analysis, DMC was associated to a higher prevalence of large calcifications and healed plaques and to a lower prevalence of lipid plaques. Finally, MACEs rate was significantly higher (25 [14.5%] vs. 12 [8.1%], p = 0.007) in DMC patients, mainly driven by a higher rate of planned revascularizations, and DMC predicted the occurrence of MACEs (mean follow-up 33.4 ± 15.6 months). Conclusions The presence of DMC identifies a distinct diabetic population with more severe CAD but with a more stable pattern of coronary atherosclerosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01637-y.
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Soulimane S, Balkau B, Vogtschmidt YD, Toeller M, Fuller JH, Soedamah-Muthu SS. Incident cardiovascular disease by clustering of favourable risk factors in type 1 diabetes: the EURODIAB Prospective Complications Study. Diabetologia 2022; 65:1169-1178. [PMID: 35411407 PMCID: PMC9174122 DOI: 10.1007/s00125-022-05698-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 03/04/2022] [Indexed: 11/30/2022]
Abstract
AIMS The aim of this prospective study was to examine CVD risk reduction in type 1 diabetes (1) for people with favourable cardiovascular health metrics and (2) by clustering of these metrics. METHODS Data from 2313 participants from the EURODIAB Prospective Complications Study were analysed. All had type 1 diabetes (51% men, mean ± SD age 32 ± 9 years). Seven cardiovascular health metrics were studied-smoking, BMI, physical activity, a diet score, total cholesterol/HDL-cholesterol ratio, combined systolic and diastolic BP and HbA1c-divided into favourable/less favourable categories. Cox proportional hazards models were used to calculate HRs (95% CIs) of incident CVD for each metric. Clusters were made by scoring each individual by the number of favourable metrics. RESULTS A total of 163 people developed incident CVD during a mean ± SD follow-up of 7.2 ± 1.3 years. Participants with more favourable HbA1c levels of <57 mmol/mol (<7.4%) had a 37% significantly lower CVD risk than those with a less favourable HbA1c (HR [95% CI] 0.63 [0.44, 0.91]), and participants with a more favourable BP (systolic BP <112 mmHg and diastolic BP <70 mmHg) had a 44% significantly lower CVD risk than participants in the less favourable BP group (HR [95% CI] 0.56 [0.34, 0.92]). There was a dose-response relation with a lower HR observed with greater clustering of more favourable metrics: people with four or more favourable metrics had an HR of 0.37 (95% CI 0.18, 0.76), adjusted for sex and age at diabetes diagnosis, compared with those with no favourable metrics. CONCLUSIONS/INTERPRETATION Low HbA1c and low BP were protective cardiovascular health metrics in our study of people with type 1 diabetes. Targeting all cardiovascular health metrics could be more effective in preventing CVD than targeting single metrics.
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Affiliation(s)
- Soraya Soulimane
- Center of Research on Psychological disorders and Somatic diseases (CoRPS), Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands
| | - Beverley Balkau
- Clinical Epidemiology, Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France
| | - Yakima D Vogtschmidt
- Hugh Sinclair Unit of Human Nutrition, Department of Food and Nutritional Sciences, University of Reading, Reading, UK
- Institute for Food, Nutrition and Health, University of Reading, Reading, UK
| | - Monika Toeller
- Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - John H Fuller
- Department of Epidemiology and Public Health, University College London, London, UK
| | - Sabita S Soedamah-Muthu
- Center of Research on Psychological disorders and Somatic diseases (CoRPS), Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands.
- Institute for Food, Nutrition and Health, University of Reading, Reading, UK.
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26
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Saeed M, Stene LC, Ariansen I, Tell GS, Tapia G, Joner G, Skrivarhaug T. Nine-fold higher risk of acute myocardial infarction in subjects with type 1 diabetes compared to controls in Norway 1973-2017. Cardiovasc Diabetol 2022; 21:59. [PMID: 35477506 PMCID: PMC9047315 DOI: 10.1186/s12933-022-01498-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/09/2022] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND We aimed to study the cumulative incidence and risk factors (sex, age, calendar year of diabetes onset, country of origin and educational level) of acute myocardial infarction (AMI) in subjects with type 1 diabetes and matched controls. METHODS A nationwide cohort of subjects with type 1 diabetes diagnosed at age < 15 years in Norway during 1973-2000 was followed until the first AMI event, emigration, death or 31st of December 2017. The Norwegian Childhood Diabetes Registry was linked to five nationwide registries, and up to ten sex- and age-matched controls per case were included. RESULTS Among 7086 subjects with type 1 diabetes, 170 (2.4%) were identified with incident AMI, compared to 193 (0.3%) of 69,356 controls. Mean age and diabetes duration at first AMI was 40.8 years and 30.6 years, respectively. The probability of AMI after 40 years of follow-up was 8.0% in subjects with type 1 diabetes and 1.1% in controls, aHR 9.05 (95% CI 7.18-11.41). In type 1 diabetes, male sex (aHR 1.45), higher age at onset of diabetes and lower education (higher compared to lower, aHR 0.38) were significantly associated with higher risk of AMI. There was no significant time trend in AMI by calendar year of diabetes onset. CONCLUSIONS We found nine-fold excess risk of AMI in subjects with type 1 diabetes, and three-fold higher risk in subjects with low versus high education. These results highlight a strengthened focus on prevention of cardiovascular disease, and diabetes education tailored to the subjects' educational background.
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Affiliation(s)
- Maryam Saeed
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. .,Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway.
| | - Lars C Stene
- Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway.,Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Inger Ariansen
- Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Grethe S Tell
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - German Tapia
- Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Geir Joner
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Torild Skrivarhaug
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway
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Recent Experimental Studies of Maternal Obesity, Diabetes during Pregnancy and the Developmental Origins of Cardiovascular Disease. Int J Mol Sci 2022; 23:ijms23084467. [PMID: 35457285 PMCID: PMC9027277 DOI: 10.3390/ijms23084467] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/14/2022] [Accepted: 04/15/2022] [Indexed: 12/14/2022] Open
Abstract
Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring.
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Celik H, Dursun AD, Tatar Y, Omercioglu G, Bastug M. Irisin pathways in hearts of Type 1 diabetic adult male rats following 6 weeks of moderate and high-volume aerobic exercise on a treadmill. SPORT SCIENCES FOR HEALTH 2022. [DOI: 10.1007/s11332-022-00924-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Aukrust SG, Holte KB, Opstad TB, Seljeflot I, Berg TJ, Helseth R. NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease. Front Immunol 2022; 12:799539. [PMID: 35069582 PMCID: PMC8767558 DOI: 10.3389/fimmu.2021.799539] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/15/2021] [Indexed: 12/30/2022] Open
Abstract
Background Neutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD. Material and Methods 102 patients with > 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis >50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes. Results Circulating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p<0.001), while dsDNA, H3Cit, PAD4 and gene expression of PAD4 did not differ with respect to the presence of T1DM. There were no significant associations between NETs markers and HbA1c in the T1DM group. None of the NETs markers differed according to the presence of CAD in patients with T1DM. While all circulating NETs markers correlated significantly with circulating neutrophils in the control group (r=0.292-393, p<0.014), only H3Cit and PAD4 correlated with neutrophils in the T1DM group (r= 0.330-0.449, p ≤ 0.001). Conclusions In this cross-sectional study of patients with long-term T1DM and age-matched controls, circulating NETs levels were not consistently associated with the presence of T1DM or glycemic status, and did not differ according to the presence of CAD in patients with T1DM. Our results entail the possibility of altered neutrophil function and reduced NETosis in T1DM. This warrants further investigation.
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Affiliation(s)
- Sverre Grøver Aukrust
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway
| | | | - Trine B Opstad
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ingebjørg Seljeflot
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Tore Julsrud Berg
- Department of Endocrinology, Oslo University Hospital Aker, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Ragnhild Helseth
- Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital Ullevål, Oslo, Norway
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Singh A, Kukreti R, Saso L, Kukreti S. Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes. Molecules 2022; 27:950. [PMID: 35164215 PMCID: PMC8840622 DOI: 10.3390/molecules27030950] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/20/2022] [Accepted: 01/26/2022] [Indexed: 02/07/2023] Open
Abstract
Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease.
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Affiliation(s)
- Anju Singh
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India;
- Department of Chemistry, Ramjas College, University of Delhi, Delhi 110007, India
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, CSIR-Institute of Genomics and Integrative Biology (IGIB), Mall Road, Delhi 110007, India;
| | - Luciano Saso
- Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy;
| | - Shrikant Kukreti
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi 110007, India;
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HDL and Diabetes. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1377:119-127. [DOI: 10.1007/978-981-19-1592-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Maragkoudakis S, Katsi V, Melidonis A, Soulaidopoulos S, Kolovou GD, Papazafeiropoulou AK, Trikkalinou A, Toutouzas K, Tsioufis K. Antiplatelet and Antithrombotic Therapy in Type I Diabetes Mellitus: Update on Current Data. Curr Diabetes Rev 2022; 18:e030122199792. [PMID: 34979890 DOI: 10.2174/1573399818666220103091236] [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: 08/13/2021] [Revised: 10/07/2021] [Accepted: 10/21/2021] [Indexed: 11/22/2022]
Abstract
Diabetes mellitus type 1 (T1DM) is an autoimmune disease characterized by a markedly elevated cardiovascular (CV) risk due to premature atherosclerosis. Previous studies have shown that intense glycemic control reduces the incidence of CV disease. Antiplatelet therapy is considered to be a very important therapy for secondary prevention of recurrent atherothrombotic events in patients with DM, while it may be considered for primary prevention in individuals with T1DM with additional CV risk factors. The aim of the present review is to summarize existing literature data regarding the thrombotic risk in T1DM patients and discuss current treatment strategies.
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Affiliation(s)
| | - Vasiliki Katsi
- First Department of Cardiology, National and Kapodistrian University of Athens,School of Medicine, Hippokration General Hospital, Athens, Greece
| | | | - Stergios Soulaidopoulos
- Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Genovefa D Kolovou
- Cardiometabolic Center, Lipid Center, Metropolitan Hospital, Athens, Greece
| | | | | | - Konstantinos Toutouzas
- Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
| | - Konstantinos Tsioufis
- Department of Cardiology, School of Medicine, National and Kapodistrian University of Athens, Hippokration General Hospital, Athens, Greece
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Sun XJ, Liu NF. Diabetic mellitus, vascular calcification and hypoxia: A complex and neglected tripartite relationship. Cell Signal 2021; 91:110219. [PMID: 34921978 DOI: 10.1016/j.cellsig.2021.110219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/11/2021] [Accepted: 12/11/2021] [Indexed: 11/15/2022]
Abstract
DM (diabetic mellitus) and its common vascular complications VC (vascular calcification), are increasingly harmful to human health. In recent years, the research on the relationship between DM and VC is also deepening. Hypoxia, as one of the pathogenic factors of many disease models, is also closely related to the occurrence of DM and VC. There are some studies on the role of hypoxia in the pathogenesis of DM and VC respectively, but no one has made an in-depth summary of the systematic connection between hypoxia, DM and VC. Therefore, what we want to review in this article are the relationship between DM, VC and hypoxia, respectively, as well as the role of hypoxia in the development of DM and VC, which has little concern but is a novel and potentially target that may provide some new ideas for the prevention and treatment of DM, VC, especially diabetic VC.
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Affiliation(s)
- Xue-Jiao Sun
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing 210009, PR China
| | - Nai-Feng Liu
- Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing 210009, PR China.
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Orchard TJ. Cardiovascular disease in type 1 diabetes: a continuing challenge. Lancet Diabetes Endocrinol 2021; 9:548-549. [PMID: 34303413 DOI: 10.1016/s2213-8587(21)00190-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Accepted: 07/04/2021] [Indexed: 11/20/2022]
Affiliation(s)
- Trevor J Orchard
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
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Abstract
PURPOSE OF REVIEW Type 1 diabetes mellitus (T1DM) is associated with increased mortality, with premature cardiovascular disease (CVD) a major factor. To date, research has identified multiple risk factors for this excess CVD liability. However, gaps remain in our understanding of the underlying mechanisms. RECENT FINDINGS T1DM is generally diagnosed at a young age. Since cardiovascular complications often only manifest at a later stage of life, there is generally less focus in earlier years on reducing CVD risk for affected individuals. This is an area that requires improvement as risk factors might be managed from earlier age to reduce later development of CVD. In this review, we discuss the evidence for cardiovascular risk factors, risk prediction models, candidate surrogate measurements and CVD risk management.
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Affiliation(s)
- I H Teoh
- Diabetes, Endocrinology & Metabolism Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - P Elisaus
- Diabetes, Endocrinology & Metabolism Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - J D Schofield
- Diabetes, Endocrinology & Metabolism Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
- Division of Diabetes, Endocrinology & Gastroenterology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
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Hashemi J, Barati G, Bibak B. Decellularized Matrix Bioscaffolds: Implementation of Native Microenvironment in Pancreatic Tissue Engineering. Pancreas 2021; 50:942-951. [PMID: 34643609 DOI: 10.1097/mpa.0000000000001868] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
ABSTRACT Type 1 diabetes is an autoimmune disease, and its incidence is usually estimated in the range of 5% to 10%. Currently, the administration of exogenous insulin is the standard of care therapy. However, this therapy is not effective in some patients who may develop some chronic complications. Islet transplantation into the liver is another therapy with promising outcomes; however, the long-term efficacy of this therapeutic option is limited to a small number of patients. Because native extracellular matrix (ECM) components provide a suitable microenvironment for islet functions, engineering a 3-dimensional construct that recapitulates the native pancreatic environment could address these obstacles. Many attempts have been conducted to mimic an in vivo microenvironment to increase the survival of islets or islet-like clusters. With the advent of decellularization technology, it is possible to use a native ECM in organ engineering. Pancreatic decellularized bioscaffold provides proper cell-cell and cell-ECM interactions and retains growth factors that are critical in the determination of cell fate within a native organ. This review summarizes the current knowledge of decellularized matrix technology and addresses its possible limitations before use in the clinic.
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Affiliation(s)
- Javad Hashemi
- From the Department of Pathobiology and Laboratory Sciences, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd
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37
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Gubitosi-Klug R, Gao X, Pop-Busui R, de Boer IH, White N, Aiello LP, Miller R, Palmer J, Tamborlane W, Wallia A, Kosiborod M, Lachin JM, Bebu I. Associations of Microvascular Complications With the Risk of Cardiovascular Disease in Type 1 Diabetes. Diabetes Care 2021; 44:1499-1505. [PMID: 33980605 PMCID: PMC8323173 DOI: 10.2337/dc20-3104] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 03/26/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We examined whether the presence of microvascular complications was associated with increased subsequent risk of cardiovascular disease (CVD) among participants with type 1 diabetes in the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study followed for >35 years. RESEARCH DESIGN AND METHODS Standardized longitudinal data collection included: 1) stereoscopic seven-field retinal fundus photography centrally graded for retinopathy stage and clinically significant macular edema; 2) urinary albumin excretion rate (AER) and estimated glomerular filtration rate (eGFR); 3) cardiovascular autonomic neuropathy (CAN) reflex testing; and 4) adjudicated CVD events, including death from CVD, nonfatal myocardial infarction, stroke, subclinical myocardial infarction on electrocardiogram, confirmed angina, or coronary artery revascularization. Cox proportional hazards models assessed the association of microvascular complications with subsequent risk of CVD. RESULTS A total of 239 participants developed CVD, including 120 participants who suffered major adverse cardiovascular events (MACE) defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The presence of microvascular disease (diabetic retinopathy, kidney disease, or CAN) was associated with increased risk of subsequent CVD and MACE (hazard ratios 1.86 to 3.18 and 2.09 to 3.63, respectively), associations that remained significant after adjusting for age and HbA1c. After adjustment for traditional CVD risk factors, however, only sustained AER ≥30 mg/24 h occurring alone and/or with eGFR <60 mL/min/1.73 m2 and the presence of both retinal and kidney disease remained associated with CVD. CONCLUSIONS Advanced microvascular disease, especially moderate to severe albuminuria or eGFR <60 mL/min/1.73 m2, conveyed an increased risk of subsequent cardiovascular disease in the DCCT/EDIC cohort.
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Affiliation(s)
- Rose Gubitosi-Klug
- Pediatric Endocrinology, UH Rainbow Babies and Children's Hospital, Cleveland, OH
| | - Xiaoyu Gao
- Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Rockville, MD
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI
| | - Ian H de Boer
- Division of Nephrology, University of Washington, Seattle, WA
| | - Neill White
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO
| | | | - Ryan Miller
- Division of Pediatric Endocrinology, University of Maryland, Baltimore, MD
| | - Jerry Palmer
- Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA
| | - William Tamborlane
- Department of Pediatrics and Endocrinology, Yale School of Medicine, New Haven, CT
| | - Amisha Wallia
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | - John M Lachin
- Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Rockville, MD
| | - Ionut Bebu
- Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Rockville, MD
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López-Díez R, Egaña-Gorroño L, Senatus L, Shekhtman A, Ramasamy R, Schmidt AM. Diabetes and Cardiovascular Complications: The Epidemics Continue. Curr Cardiol Rep 2021; 23:74. [PMID: 34081211 PMCID: PMC8173334 DOI: 10.1007/s11886-021-01504-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/14/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW The cardiovascular complications of type 1 and 2 diabetes are major causes of morbidity and mortality. Extensive efforts have been made to maximize glycemic control; this strategy reduces certain manifestations of cardiovascular complications. There are drawbacks, however, as intensive glycemic control does not impart perennial protective benefits, and these efforts are not without potential adverse sequelae, such as hypoglycemic events. RECENT FINDINGS Here, the authors have focused on updates into key areas under study for mechanisms driving these cardiovascular disorders in diabetes, including roles for epigenetics and gene expression, interferon networks, and mitochondrial dysfunction. Updates on the cardioprotective roles of the new classes of hyperglycemia-targeting therapies, the sodium glucose transport protein 2 inhibitors and the agonists of the glucagon-like peptide 1 receptor system, are reviewed. In summary, insights from ongoing research and the cardioprotective benefits of the newer type 2 diabetes therapies are providing novel areas for therapeutic opportunities in diabetes and CVD.
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Affiliation(s)
- Raquel López-Díez
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY 10016 USA
| | - Lander Egaña-Gorroño
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY 10016 USA
| | - Laura Senatus
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY 10016 USA
| | - Alexander Shekhtman
- Department of Chemistry, The State University of New York at Albany, Albany, NY USA
| | - Ravichandran Ramasamy
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY 10016 USA
| | - Ann Marie Schmidt
- Diabetes Research Program, Department of Medicine, New York University Grossman School of Medicine, 435 East 30th Street, Science Building, Room 615, New York, NY 10016 USA
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Bebu I, Keshavarzi S, Gao X, Braffett BH, Canty AJ, Herman WH, Orchard TJ, Dagogo-Jack S, Nathan DM, Lachin JM, Paterson AD. Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study. Diabetes Care 2021; 44:1309-1316. [PMID: 33883194 PMCID: PMC8247524 DOI: 10.2337/dc20-2388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 03/06/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia). RESULTS CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE. CONCLUSIONS Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.
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Affiliation(s)
- Ionut Bebu
- Biostatistics Center, George Washington University, Rockville, MD
| | - Sareh Keshavarzi
- Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Xiaoyu Gao
- Biostatistics Center, George Washington University, Rockville, MD
| | | | - Angelo J Canty
- Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario, Canada
| | - William H Herman
- Medical School and School of Public Health, University of Michigan, Ann Arbor, MI
| | - Trevor J Orchard
- Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Samuel Dagogo-Jack
- Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center, Memphis, TN
| | - David M Nathan
- Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - John M Lachin
- Biostatistics Center, George Washington University, Rockville, MD
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Ben Guebila M, Thiele I. Dynamic flux balance analysis of whole-body metabolism for type 1 diabetes. NATURE COMPUTATIONAL SCIENCE 2021; 1:348-361. [PMID: 38217214 DOI: 10.1038/s43588-021-00074-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 04/21/2021] [Indexed: 01/15/2024]
Abstract
Type 1 diabetes (T1D) mellitus is a systemic disease triggered by a local autoimmune inflammatory reaction in insulin-producing cells that induce organ-wide, long-term metabolic effects. Mathematical modeling of the whole-body regulatory bihormonal system has helped to identify therapeutic interventions but is limited to a coarse-grained representation of metabolism. To extend the depiction of T1D, we developed a whole-body model of organ-specific regulation and metabolism that highlighted chronic inflammation as a hallmark of the disease, identified processes related to neurodegenerative disorders and suggested calcium channel blockers as adjuvants for diabetes control. In addition, whole-body modeling of a patient population allowed for the assessment of between-individual variability to insulin and suggested that peripheral glucose levels are degenerate biomarkers of the internal metabolic state. Taken together, the organ-resolved, dynamic modeling approach enables modeling and simulation of metabolic disease at greater levels of coverage and precision and the generation of hypothesis from a molecular level up to the population level.
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Affiliation(s)
- Marouen Ben Guebila
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ines Thiele
- School of Medicine, National University of Ireland, Galway, Ireland.
- Discipline of Microbiology, School of Natural Sciences, National University of Ireland, Galway, Galway, Ireland.
- APC Microbiome, Cork, Ireland.
- Ryan Institute, National University of Ireland, Galway, Ireland.
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Cai X, Lin C, Yang W, Nie L, Ji L. Non-Insulin Antidiabetes Treatment in Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Diabetes Metab J 2021; 45:312-325. [PMID: 33705649 PMCID: PMC8164953 DOI: 10.4093/dmj.2020.0171] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 10/22/2020] [Indexed: 12/13/2022] Open
Abstract
In order to evaluate the efficacy and side effects of the non-insulin antidiabetes medications as an adjunct treatment in type 1 diabetes mellitus (T1DM), we conducted systematic searches in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials published between the date of inception and March 2020 to produce a systematic review and meta-analysis. Overall, 57 studies were included. Compared with placebo, antidiabetes agents in adjunct to insulin treatment resulted in significant reduction in glycosylated hemoglobin (weighted mean difference [WMD], -0.30%; 95% confidence interval [CI], -0.34 to -0.25%; P<0.01) and body weight (WMD, -2.15 kg; 95% CI, -2.77 to -1.53 kg; P<0.01), and required a significantly lower dosage of insulin (WMD, -5.17 unit/day; 95% CI, -6.77 to -3.57 unit/day; P<0.01). Compared with placebo, antidiabetes agents in adjunct to insulin treatment increased the risk of hypoglycemia (relative risk [RR], 1.04; 95% CI, 1.01 to 1.08; P=0.02) and gastrointestinal side effects (RR, 1.99; 95% CI, 1.61 to 2.46; P<0.01) in patients with T1DM. Compared with placebo, the use of non-insulin antidiabetes agents in addition to insulin could lead to glycemic improvement, weight control and lower insulin dosage, while they might be associated with increased risks of hypoglycemia and gastrointestinal side effects in patients with T1DM.
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Affiliation(s)
- Xiaoling Cai
- Department of Endocrine and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrine and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrine and Metabolism, Peking University People’s Hospital, Beijing, China
| | - Lin Nie
- Department of Endocrine and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrine and Metabolism, Peking University People’s Hospital, Beijing, China
- Corresponding author: Linong Ji https://orcid.org/0000-0002-3262-2168 Department of Endocrinology and Metabolism, Peking University People’s Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing 100044, China E-mail:
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Chiesa ST, Marcovecchio ML. Preventing Cardiovascular Complications in Type 1 Diabetes: The Need for a Lifetime Approach. Front Pediatr 2021; 9:696499. [PMID: 34178905 PMCID: PMC8219852 DOI: 10.3389/fped.2021.696499] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/17/2021] [Indexed: 01/29/2023] Open
Abstract
Cardiovascular disease (CVD) remains the main cause of morbidity and mortality in individuals with type 1 diabetes (T1D). Adolescence appears to be a critical time for the development of early subclinical manifestations of CVD, with these changes likely driven by a deterioration in glycemic control during the progression through puberty, combined with the emergence of numerous other traditional cardiometabolic risk factors (e.g., hypertension, dyslipidemia, smoking, alcohol use, obesity, etc.) which emerge at this age. Although hemoglobin A1C has long been the primary focus of screening and treatment strategies, glycemic control remains poor in youth with T1D. Furthermore, screening for cardiovascular risk factors-which are often elevated in youth with T1D-is suboptimal, and use of pharmacological interventions for hypertension and dyslipidemia remains low. As such, there is a clear need not only for better screening strategies for CVD risk factors in youth, but also early interventions to reduce these, if future CVD events have to be prevented. Accumulating evidence has recently suggested that early increases in urinary albumin excretion, even within the normal range, may identify adolescents with T1D who are at an increased risk of complications, and results from pharmacological intervention with statins and ACE inhibitors in these individuals have been encouraging. These data join a growing evidence highlighting the need for a whole-life approach to prevention starting from childhood if efforts to improve CVD outcomes and related mortality in T1D are to be maintained.
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Affiliation(s)
- Scott T Chiesa
- Institute of Cardiovascular Science, University College London, London, United Kingdom
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Bebu I, Braffett BH, Orchard TJ, Lorenzi GM, Nathan DM, Herman WH, Lachin JM. Moderation of the effect of glycemia on the risk of cardiovascular disease in type 1 diabetes: The DCCT/EDIC study. Diabetes Res Clin Pract 2021; 171:108591. [PMID: 33310124 PMCID: PMC7854481 DOI: 10.1016/j.diabres.2020.108591] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 11/25/2020] [Accepted: 11/30/2020] [Indexed: 11/29/2022]
Abstract
AIMS We assessed whether and to what extent established cardiovascular disease (CVD) risk factors moderate (enhance/reduce) the effect of hyperglycemia on CVD outcomes in the long-term follow-up of the Diabetes Control and Complications Trial type 1 diabetes (T1D) cohort (N = 1441). METHODS Moderation of the effect of glycemia on subsequent risk of major adverse cardiovascular events (MACE: fatal or non-fatal myocardial infarction or stroke) and any-CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure) was assessed separately using interaction terms between HbA1c and other risk factors in Cox proportional hazards models. RESULTS Over a median follow-up of 29 years, there were 120 MACE cases and 239 any-CVD cases. Higher pulse, higher triglycerides, use of calcium channel blockers, and presence of neuropathy individually enhanced (p < 0.01) the effect of glycemia on any-CVD. Higher pulse and triglyceride levels, albumin excretion rate, hypertension, and no family history of type 2 diabetes enhanced (p < 0.01) the effect of glycemia on MACE. CONCLUSIONS Such moderation analyses identify subgroups with increased CVD risk who might especially benefit from earlier and/or more intensive glycemic control. Interventions treating modifiable moderating factors may independently reduce the risk of CVD and also reduce the risk associated with a higher HbA1c.
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Affiliation(s)
- Ionut Bebu
- The Biostatistics Center, The George Washington University, Rockville, MD, United States.
| | - Barbara H Braffett
- The Biostatistics Center, The George Washington University, Rockville, MD, United States
| | | | | | - David M Nathan
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | - John M Lachin
- The Biostatistics Center, The George Washington University, Rockville, MD, United States
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44
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Martynov SA, Severina AS, Larina II, Shamhalova MS, Arzumanov SV, Pinchuk AV, Shestakova MV. [Preparation of the dialysis patient with type 1 diabetes mellitus for kidney transplantation]. ACTA ACUST UNITED AC 2020; 66:18-30. [PMID: 33481364 DOI: 10.14341/probl12686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 12/14/2020] [Accepted: 12/20/2020] [Indexed: 11/06/2022]
Abstract
Kidney transplantation is unique method of renal replacement therapy, allowing to improve quality and duration of life for patients with diabetes mellitus type 1 (DM1) and end-stage renal disease (ESRD) on dialysis therapy. Recently using of innovation technologies for diabetes management and modern immunosuppression enable achieving better results of posttransplant rehabilitation for patients with DM1, especially if kidney transplantation is performed early after initiation of dialysis. Detailed examination of patient with DM1 before potential kidney transplantation is very important to reduce of early and late postoperative complications. Kidney transplantation preparation includes effective glycemic control, adequate dialysis therapy, treatment of diabetes and ESRD complications and concomitant conditions, especially cardiovascular diseases, accounting for kidney transplantation perspective. Furthermore, diagnostics and treatment of any infectious process, timely vaccination, cancer screening are basic approaches of kidney transplantation preparation program, providing the best survival rate of kidney graft and patient.
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Affiliation(s)
| | | | | | | | - S V Arzumanov
- N.A. Lopatkin Research Institute of Urology and Interventional Radiology - branch of the National Medical Radiological Research Centre
| | - A V Pinchuk
- Sklifosovsky Research Institute for Emergency Medicine
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45
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Han WM, Chen XC, Li GR, Wang Y. Acacetin Protects Against High Glucose-Induced Endothelial Cells Injury by Preserving Mitochondrial Function via Activating Sirt1/Sirt3/AMPK Signals. Front Pharmacol 2020; 11:607796. [PMID: 33519472 PMCID: PMC7844858 DOI: 10.3389/fphar.2020.607796] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022] Open
Abstract
The strategy of decreasing atherosclerotic cardiovascular disorder is imperative for reducing premature death and improving quality of life in patients with diabetes mellitus. The aim of this study was to investigate whether the natural flavone acacetin could protect against endothelial injury induced by high glucose and attenuate diabetes-accelerated atherosclerosis in streptozotocin-(STZ) induced diabetic ApoE−/− mice model. It was found that in human umbilical vein endothelial cells (HUVECs) cultured with normal 5.5 mM or high 33 mM glucose, acacetin (0.3–3 μM) exerted strong cytoprotective effects by reversing high glucose-induced viability reduction and reducing apoptosis and excess production of intracellular reactive oxygen species (ROS) and malondialdehyde in a concentration-dependent manner. Acacetin countered high glucose-induced depolarization of mitochondrial membrane potential and reduction of ATP product and mitoBcl-2/mitoBax ratio. Silencing Sirt3 abolished the beneficial effects of acacetin. Further analysis revealed that these effects of acacetin rely on Sirt1 activation by increasing NAD+ followed by increasing Sirt3, pAMPK and PGC-1α. In STZ-diabetic mice, acacetin significantly upregulated the decreased signaling molecules (i.e. SOD, Bcl-2, PGC-1α, pAMPK, Sirt3 and Sirt1) in aorta tissue and attenuated atherosclerosis. These results indicate that vascular endothelial protection of acacetin by activating Sirt1/Sirt3/AMPK signals is likely involved in alleviating diabetes-accelerated atherosclerosis by preserving mitochondrial function, which suggests that acacetin may be a drug candidate for treating cardiovascular disorder in patients with diabetes.
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Affiliation(s)
- Wei-Min Han
- Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Xu-Chang Chen
- Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China
| | - Gui-Rong Li
- Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China.,Nanjing Amazigh Pharma Limited, Nanjing, China
| | - Yan Wang
- Xiamen Cardiovascular Hospital, School of Medicine, Xiamen University, Xiamen, China
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46
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Chiesa ST, Charakida M, McLoughlin E, Nguyen HC, Georgiopoulos G, Motran L, Elia Y, Marcovecchio ML, Dunger DB, Dalton RN, Daneman D, Sochett E, Mahmud FH, Deanfield JE. Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation. Eur Heart J 2020; 40:3559-3566. [PMID: 30863865 PMCID: PMC6855140 DOI: 10.1093/eurheartj/ehz114] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 08/26/2018] [Accepted: 02/18/2019] [Indexed: 12/16/2022] Open
Abstract
AIMS High-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed. METHODS AND RESULTS Seventy adolescents with Type 1 diabetes (age 10-17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05). CONCLUSION Increased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.
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Affiliation(s)
- Scott T Chiesa
- Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, UK
| | - Marietta Charakida
- Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, UK
| | - Eve McLoughlin
- Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, UK
| | - Helen C Nguyen
- Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, UK
| | | | - Laura Motran
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Yesmino Elia
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | | | - David B Dunger
- Department of Paediatrics, University of Cambridge, Cambridge, UK.,Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - R Neil Dalton
- WellChild Laboratory, St. Thomas' Hospital, King's College London, London, UK
| | - Denis Daneman
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Etienne Sochett
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - Farid H Mahmud
- Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada
| | - John E Deanfield
- Vascular Physiology Unit, UCL Institute of Cardiovascular Science, London, UK
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Bebu I, Braffett BH, Schade D, Sivitz W, Malone JI, Pop-Busui R, Lorenzi GM, Lee P, Trapani VR, Wallia A, Herman WH, Lachin JM. An Observational Study of the Equivalence of Age and Duration of Diabetes to Glycemic Control Relative to the Risk of Complications in the Combined Cohorts of the DCCT/EDIC Study. Diabetes Care 2020; 43:2478-2484. [PMID: 32788280 PMCID: PMC7510046 DOI: 10.2337/dc20-0226] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 07/13/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE This epidemiological analysis of the pooled Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort describes the equivalence of a 1-percentage point increase in HbA1c (such as from 7% to 8%) and years of additional age or duration of type 1 diabetes (T1D) relative to the risk of complications. RESEARCH DESIGN AND METHODS Separate Cox proportional hazards models determined the number of additional years of age and/or duration of T1D that would result in the same increase in risk of microvascular (retinopathy, nephropathy, and neuropathy) and cardiovascular complications and mortality as a 1-percentage point increase in HbA1c. RESULTS The risk of any cardiovascular disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 4.3 (95% CI 2.7-5.9) additional years of age or 5.6 (95% CI 2.7-6.5) additional years' duration of T1D. The risk of estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or end-stage renal disease associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 12.1 (95% CI 8.3-15.9) additional years of age or 18.0 (95% CI 4.3-31.7) additional years' duration of T1D. The proliferative diabetic retinopathy risk associated with a 1-percentage point increase in HbA1c was equivalent to the risk associated with 6.4 (95% CI 5.3-7.4) additional years' duration of T1D, while for mortality risk, it was equivalent to the risk associated with 12.9 (95% CI 6.6-19.3) additional years of age. CONCLUSIONS Our results help evaluate the impact of glycemia on advanced complications in a way that may be more interpretable to health care providers and individuals with T1D.
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Affiliation(s)
- Ionut Bebu
- Biostatistics Center, The George Washington University, Rockville, MD
| | | | | | | | | | | | | | - Pearl Lee
- University of Michigan, Ann Arbor, MI
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Abstract
PURPOSE OF REVIEW Persons with diabetes mellitus (DM) have increased morbidity and mortality rates compared with persons without DM. Sudden cardiac death (SCD) is a leading cause of death, and multiple studies have found an increased risk of SCD among individuals with DM. This review sought to collect the latest knowledge of the epidemiological and pathophysiological interplay between DM and SCD. RECENT FINDINGS Persons with DM have a two- to tenfold increased risk of SCD compared with persons without DM. The underlying mechanisms for the increased risk of SCD are complex and multifactorial. The main pathophysiological contributors are DM-induced cardiac autonomic neuropathy (CAN), metabolic changes, silent ischemia, and polypharmacy. Persons with DM have an increased risk of SCD. Future studies should focus on CAN and the combined risk of QT prolongation from the interplay between CAN, hypoglycemia, and polypharmacy. Genes and pathways involved in control of the autonomic nervous system and cardiac ion channels could be a future focal point.
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Bebu I, Schade D, Braffett B, Kosiborod M, Lopes-Virella M, Soliman EZ, Herman WH, Bluemke DA, Wallia A, Orchard T, Lachin JM. Risk Factors for First and Subsequent CVD Events in Type 1 Diabetes: The DCCT/EDIC Study. Diabetes Care 2020; 43:867-874. [PMID: 32001614 PMCID: PMC7085803 DOI: 10.2337/dc19-2292] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/05/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events. RESEARCH DESIGN AND METHODS CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes. RESULTS Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]). CONCLUSIONS Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained.
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Affiliation(s)
- Ionut Bebu
- Biostatistics Center, The George Washington University, Rockville, MD
| | | | - Barbara Braffett
- Biostatistics Center, The George Washington University, Rockville, MD
| | - Mikhail Kosiborod
- Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO.,The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Maria Lopes-Virella
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | | | - William H Herman
- Schools of Medicine and Public Health, University of Michigan, Ann Arbor, MI
| | - David A Bluemke
- Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Amisha Wallia
- Department of Medicine, Northwestern University, Evanston, IL
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Inanır M, Gunes Y, Sincer I, Erdal E. Evaluation of Electrocardiographic Ventricular Depolarization and Repolarization Variables in Type 1 Diabetes Mellitus. Arq Bras Cardiol 2020; 114:275-280. [PMID: 32215498 PMCID: PMC7077569 DOI: 10.36660/abc.20180343] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/10/2019] [Indexed: 12/14/2022] Open
Abstract
Background The risk of cardiovascular events and sudden death increases with type 1 diabetes mellitus (T1DM). Objective To evaluate electrocardiographic markers of arrhythmias in T1DM patients. Methods Electrocardiographic parameters reflecting ventricular depolarization and repolarization, namely, QT, QTc, QTd, QTdc, Tp-e, JT, and JTc intervals and Tp-e/QT and Tp-e/QTc ratios, of 46 patients diagnosed with T1DM were retrospectively analyzed and compared with 46 healthy age-, sex-, and body mass-matched controls. Correlations between T1DM duration, hemoglobin A1c (HbA1c), and ventricular repolarization variables were analyzed. P values lower than 0.05 were considered statistically significant. Results Diabetes duration was 16.6 ± 7.1 years, and HbA1c was 10.81% ± 3.27% in the T1DM group. In comparison with the control group, heart rate, QTc, QTd, QTdc, Tp-e and JTc intervals, Tp-e/QT ratio (p < 0.001), and Tp-e/QTc ratio (p = 0.007) were significantly higher in T1DM patients. T1DM duration and HbA1c levels were significantly correlated with QTc, QTd, QTdc, Tp-e, and JTc intervals and Tp-e/QT and Tp-e/QTc ratios. Conclusions In T1DM patients, potential electrocardiographic repolarization predictors were significantly increased in correlation with disease duration and HbA1c levels. These findings may contribute to the understanding of sudden cardiac death in patients with T1DM.
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Affiliation(s)
- Mehmet Inanır
- Abant Izzet Baysal University Hospital, Bolu - Turkey
| | - Yilmaz Gunes
- Abant Izzet Baysal University Hospital, Bolu - Turkey
| | - Isa Sincer
- Abant Izzet Baysal University Hospital, Bolu - Turkey
| | - Emrah Erdal
- Abant Izzet Baysal University Hospital, Bolu - Turkey
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