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Mesa A, Franch-Nadal J, Navas E, Mauricio D. Cardiovascular disease in women with type 1 diabetes: a narrative review and insights from a population-based cohort analysis. Cardiovasc Diabetol 2025; 24:217. [PMID: 40399939 PMCID: PMC12093901 DOI: 10.1186/s12933-025-02791-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Accepted: 05/14/2025] [Indexed: 05/23/2025] Open
Abstract
Cardiovascular disease (CVD) remains the leading cause of mortality among people with type 1 diabetes (T1D), with cardiovascular mortality rates 2-5 times higher than in the general population. A concerning sex disparity exists within this high-risk population, as the cardioprotective advantage typically observed in women without diabetes appears attenuated or eliminated in individuals with T1D. This disparity is evident across the CVD spectrum, including coronary artery disease, stroke, heart failure, and cardiovascular mortality, with women consistently experiencing an excess burden of disease. These differences are particularly pronounced in women with early-onset T1D, leading to a substantial loss of life-years-approximately 18 years for women compared to 14 for men. Several factors may contribute to this sex disparity. First, the effect of hyperglycemia on CVD appears to have a sex-based differential impact and women with T1D often demonstrate more difficulties to achieve optimal glycemic control. Second, although women with T1D generally exhibit a more favorable CVD risk factor profile than men with T1D, the presence of hypertension, smoking or diabetic kidney disease seem to have a strong impact on CVD in women. Diabetes also appears to diminish sex-based differences in lipid metabolism, and a trend towards increased obesity rates among women with T1D has been observed. Lastly, female-specific factors, which are more prevalent in T1D, exacerbate cardiovascular risk. These include premature menopause, pregnancy-related disorders (such as preeclampsia), polycystic ovary syndrome, and autoimmune diseases, which disproportionately affect women. This narrative review examines the epidemiological evidence highlighting the aspects regarding the excess risk of CVD in women with T1D and evaluates sex disparities in both traditional and female-specific risk factors. Finally, we include a sex-based analysis from the Catalan Registry, which highlights the critical need for greater awareness and enhanced early detection and management of CVD risk factors in this population.
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Affiliation(s)
- Alex Mesa
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí 89, 08041, Barcelona, Spain.
- Centro de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
| | - Josep Franch-Nadal
- Centro de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain
- Diabetis en Atenció Primaria (DAP-Cat) Group, Unitat de Suport a la Recerca Barcelona, Fundació IDIAP Jordi Gol I Gurina, Barcelona, Spain
- Primary Health Care Center Raval Sud, Gerència d'Atenció Primaria, Institut Català de la Salut, Barcelona, Spain
| | - Elena Navas
- Diabetis en Atenció Primaria (DAP-Cat) Group, Unitat de Suport a la Recerca Barcelona, Fundació IDIAP Jordi Gol I Gurina, Barcelona, Spain
| | - Dídac Mauricio
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Carrer de Sant Quintí 89, 08041, Barcelona, Spain.
- Centro de Investigación Biomédica en Red (CIBER) of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
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Zeng X, Ma C, Fu W, Xu Y, Wang R, Liu D, Zhang L, Hu N, Li D, Li W. Changes in Type 1 Diabetes-Associated Gut Microbiota Aggravate Brain Ischemia Injury by Affecting Microglial Polarization Via the Butyrate-MyD88 Pathway in Mice. Mol Neurobiol 2025; 62:3764-3780. [PMID: 39322832 DOI: 10.1007/s12035-024-04514-9] [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: 02/25/2024] [Accepted: 09/18/2024] [Indexed: 09/27/2024]
Abstract
People with type 1 diabetes (T1D) have a significantly elevated risk of stroke, but the mechanism through which T1D worsens ischemic stroke remains unclear. This study was aimed at investigating the roles of T1D-associated changes in the gut microbiota in aggravating ischemic stroke and the underlying mechanism. Fecal 16SrRNA sequencing indicated that T1D mice and mice with transplantation of T1D mouse gut microbiota had lower relative abundance of butyric acid producers, f_Erysipelotrichaceae and g_Allobaculum, and lower content of butyric acid in feces. After middle cerebral artery occlusion (MCAO), these mice had poorer neurological outcomes and more severe inflammation, but higher expression of myeloid differentiation factor 88 (MyD88) in the ischemic penumbra; moreover, the microglia were inclined to polarize toward the pro-inflammatory type. Administration of butyrate to T1D mice in the drinking water alleviated the neurological damage after MCAO. Butyrate influenced the response and polarization of BV2 and decreased the production of inflammatory cytokines via MyD88 after oxygen-glucose deprivation/reoxygenation. Knocking down MyD88 in the brain alleviated neurological outcomes and decreased the concentrations of inflammatory cytokines in the brain after stroke in mice with transplantation of T1D mouse gut microbiota. Poor neurological outcomes and aggravated inflammatory responses of T1D mice after ischemic stroke may be partly due to differences in microglial polarization mediated by the gut microbiota-butyrate-MyD88 pathway. These findings provide new ideas and potential intervention targets for alleviating neurological damage after ischemic stroke in T1D.
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Affiliation(s)
- Xianzhang Zeng
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Can Ma
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Wenchao Fu
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Yongmei Xu
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Rui Wang
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Dan Liu
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Lijuan Zhang
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Narisu Hu
- Oral Implant Center, Second Affiliated Hospital, Harbin Medical University, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Dongmei Li
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Wenzhi Li
- Department of Anesthesiology, Second Affiliated Hospital, Harbin Medical University, 246 Xuefu Road, Harbin, 150001, Heilongjiang, People's Republic of China.
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Bushnell C, Kernan WN, Sharrief AZ, Chaturvedi S, Cole JW, Cornwell WK, Cosby-Gaither C, Doyle S, Goldstein LB, Lennon O, Levine DA, Love M, Miller E, Nguyen-Huynh M, Rasmussen-Winkler J, Rexrode KM, Rosendale N, Sarma S, Shimbo D, Simpkins AN, Spatz ES, Sun LR, Tangpricha V, Turnage D, Velazquez G, Whelton PK. 2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke 2024; 55:e344-e424. [PMID: 39429201 DOI: 10.1161/str.0000000000000475] [Citation(s) in RCA: 41] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
AIM The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke. METHODS A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed. STRUCTURE Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Eliza Miller
- American College of Obstetricians and Gynecologists liaison
| | | | | | | | | | | | | | - Alexis N Simpkins
- American Heart Association Stroke Council Scientific Statement Oversight Committee on Clinical Practice Guideline liaison
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Silva JQ, Cebada AB, Escobar-Morreale H, Chávez LN. Complicaciones crónicas de la diabetes mellitus tipo 1. MEDICINE - PROGRAMA DE FORMACIÓN MÉDICA CONTINUADA ACREDITADO 2024; 14:1064-1071. [DOI: 10.1016/j.med.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Xu Q, Cheung RTF. Melatonin at repeated doses alleviates hyperglycemia-exacerbated cerebral ischemia-reperfusion injury at 72 h via anti-inflammation and anti-apoptosis. IBRO Neurosci Rep 2024; 16:418-427. [PMID: 38500787 PMCID: PMC10945201 DOI: 10.1016/j.ibneur.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 01/28/2024] [Accepted: 03/03/2024] [Indexed: 03/20/2024] Open
Abstract
Objective We aimed to investigate how hyperglycemia would exacerbate cerebral ischemia-reperfusion injury (CIRI) in a rat model of type 1 diabetes mellitus (T1DM) and explore the beneficial effects of multiple doses of melatonin in T1DM induced CIRI. Method The T1DM rat model was induced with streptozocin, and melatonin (10 mg/kg) was injected at 0.5 h before ischemia as well as at 24 and 48 h after reperfusion. Results When compared to normoglycemic (NG) rats, T1DM rats had hyperglycemia with weight loss before CIRI. Despite comparable degrees of ischemia and initial reperfusion, T1DM rats tended to have greater weight loss and had worse neurological deficits and larger infarct volume than NG rats up to 72 h after CIRI. Persistent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway but not of apoptosis or calpains was a crucial factor in T1DM-mediated exacerbation of CIRI at 72 h. Despite lacking effects on baseline hyperglycemia, ischemia and initial reperfusion, melatonin at multiple doses lessened post-CIRI weight loss, neurological deficits and infarct volume in T1DM rats at 72 h. when compared to vehicle-treated T1DM rats with CIRI. Beneficial effects of melatonin treatment included decreased activation of NF-κB pathway, apoptosis and calpains, leading to reduced expression of inducible nitric oxide synthase and enhanced neuronal density. Conclusion Melatonin at multiple doses can alleviate T1DM-mediated exacerbation of CIRI at 72 h through anti-inflammation and anti-apoptosis.
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Affiliation(s)
- Qian Xu
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Raymond Tak Fai Cheung
- Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
- Research Centre of Heart, Brain, Hormone & Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Giandalia A, Russo GT, Ruggeri P, Giancaterini A, Brun E, Cristofaro M, Bogazzi A, Rossi MC, Lucisano G, Rocca A, Manicardi V, Bartolo PD, Cianni GD, Giuliani C, Napoli A. The Burden of Obesity in Type 1 Diabetic Subjects: A Sex-specific Analysis From the AMD Annals Initiative. J Clin Endocrinol Metab 2023; 108:e1224-e1235. [PMID: 37247381 PMCID: PMC10584007 DOI: 10.1210/clinem/dgad302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 05/23/2023] [Accepted: 05/24/2023] [Indexed: 05/31/2023]
Abstract
OBJECTIVE Obesity is a growing emergency in type 1 diabetes (T1D). Sex differences in obesity prevalence and its clinical consequences in adult T1D subjects have been poorly investigated. The aim of this study was to investigate the prevalence of obesity and severe obesity, clinical correlates, and potential sex differences in a large cohort of T1D subjects participating to the AMD (Associazione Medici Diabetologi) Annals Initiative in Italy. RESEARCH DESIGN AND METHODS The prevalence of obesity [body mass index(BMI) ≥30 kg/m2] and severe obesity (BMI ≥ 35 kg/m2) according to sex and age, as well as obesity-associated clinical variables, long-term diabetes complications, pharmacological treatment, process indicators and outcomes, and overall quality of care (Q-score) were evaluated in 37 436 T1D subjects (45.3% women) attending 282 Italian diabetes clinics during 2019. RESULTS Overall, the prevalence of obesity was similar in the 2 sexes (13.0% in men and 13.9% in women; mean age 50 years), and it increased with age, affecting 1 out of 6 subjects ages >65 years. Only severe obesity (BMI >35 kg/m2) was more prevalent among women, who showed a 45% higher risk of severe obesity, compared with men at multivariate analysis. Cardiovascular disease risk factors (lipid profile, glucose, and blood pressure control), and the overall quality of diabetes care were worse in obese subjects, with no major sex-related differences. Also, micro- and macrovascular complications were more frequent among obese than nonobese T1D men and women. CONCLUSIONS Obesity is a frequent finding in T1D adult subjects, and it is associated with a higher burden of cardiovascular disease risk factors, micro- and macrovascular complications, and a lower quality of care, with no major sex differences. T1D women are at higher risk of severe obesity.
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Affiliation(s)
- Annalisa Giandalia
- Department of Clinical and Experimental Medicine, University of Messina, 98100 Messina, Italy
| | | | | | - Annalisa Giancaterini
- UOSD Endocrine, Metabolic and Nutrition Diseases, ASST Brianza, Desio Hospital, 20832 Desio, Italy
| | - Elisabetta Brun
- UOC Endocrine, Metabolic and Nutrition Diseases, Ospedale Civile di Vicenza, 36100 Vicenza, Italy
| | | | - Anna Bogazzi
- SSVD Diabetes and Endocrine Diseases, ASL TO 3, 10024 Torino, Italy
| | - Maria Chiara Rossi
- Center for Outcomes Research and Clinical Epidemiology, CORESEARCH, 75100 Pescara, Italy
| | - Giuseppe Lucisano
- Center for Outcomes Research and Clinical Epidemiology, CORESEARCH, 75100 Pescara, Italy
| | - Alberto Rocca
- SS Diabetes and Metabolic disease, Bassini Hospital, Cinisello Balsamo, 20019 Milano, Italy
| | | | | | - Graziano Di Cianni
- Diabetes and Metabolic Diseases Unit, Health Local Unit North-West Tuscany, 57100 Livorno, Italy
| | - Chiara Giuliani
- Department of Experimental Medicine, Sapienza University of Rome, 00044 Rome, Italy
| | - Angela Napoli
- Israelitico Hospital, 00044 Rome, Italy
- Cdc Santa Famiglia, 00044 Rome, Italy
- Human Nutrition Sciences, International Medical University Unicamillus, 00044 Rome, Italy
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Liang Y, Fan T, Bai M, Tang M, Cui N, Chen Y, Chen J, Wang J, Guan Y. A Knowledge Map of the Relationship between Diabetes and Stroke: A Bibliometric Analysis Study. Cerebrovasc Dis 2023; 53:270-287. [PMID: 37722359 DOI: 10.1159/000533383] [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: 03/29/2023] [Accepted: 07/31/2023] [Indexed: 09/20/2023] Open
Abstract
INTRODUCTION The correlation between diabetes and stroke has been studied extensively in epidemiological research. Here, we used bibliometric software to visualize and analyze the literature related to diabetic stroke to provide an overview of the current state of research, hotspots, and future trends in the field. METHODS Based on the Web of Science Core Collection (WoSCC) database, we collected studies related to diabetic stroke from 2007 to December 2022. We used CiteSpace (version 6.1.R5), VOSviewer, and Scimago Graphica to create knowledge maps and conduct visual analyses on authors, countries, institutions, cited references, and keywords, and Origin for statistical analysis. RESULTS We included a total of 5,171 papers on diabetic stroke from the WoSCC database. Overall, there was a steady increase in the number of publications, with a high number of emerging scientists. The USA was the most productive and influential country, which dominated national collaborations. The most common subject category was "neurology." In total, 12 major clusters were generated from the cited references. Keyword analysis showed that keywords related to poststroke injury and treatment are those with the highest burst intensity and latest burst time. CONCLUSIONS Individual disease treatment remains a hot topic, and how to balance acute stroke treatment and glycemic control is currently a difficult clinical problem. At the same time, the mechanism of their interaction and the prevention and treatment of related causative factors remain a hot topic of current and future research.
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Affiliation(s)
- Yitong Liang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China,
| | - Tingting Fan
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Min Bai
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Meng Tang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Na Cui
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yue Chen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinyi Chen
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jingwen Wang
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yue Guan
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, China
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Russo GT, Manicardi V, Rossi MC, Orsi E, Solini A. Sex- and gender-differences in chronic long-term complications of type 1 and type 2 diabetes mellitus in Italy. Nutr Metab Cardiovasc Dis 2022; 32:2297-2309. [PMID: 36064685 DOI: 10.1016/j.numecd.2022.08.011] [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: 05/04/2022] [Revised: 08/02/2022] [Accepted: 08/10/2022] [Indexed: 10/15/2022]
Abstract
AIMS This review summarizes the contribution of Italian diabetologists devoted to a better understanding of the complex relationship linking sex/gender and long-term complications of type 1 (T1DM) and type 2 diabetes (T2DM) over the last fifteen years. DATA SYNTHESIS Microvascular and macrovascular complications of diabetes show sex- and gender-related differences, involving pathophysiological mechanisms, epidemiological features and clinical presentation, due to the interaction between biological and psychosocial factors. These differences greatly impact on the progression of diabetes and its long-term complications, especially in the cardiovascular, renal and liver districts. CONCLUSION A better knowledge of such sex- and gender-related characteristics is required for a more precise patient phenotypization, and for the choice of a personalized antihyperglycemic treatment. Despite such mounting evidence, current diabetes clinical guidelines do not as yet adequately consider sex/gender differences.
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Affiliation(s)
- G T Russo
- Department of Clinical and Experimental Medicine, University of Messina, Italy.
| | | | - M C Rossi
- CORESEARCH - Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy
| | - E Orsi
- IRCCS Foundation Cà Grande Ospedale Maggiore, Milan, Italy
| | - A Solini
- Department of Surgical, Medical, Molecular and Critical Area Pathology, University of Pisa, Italy.
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Penlioglou T, Stoian AP, Papanas N. Diabetes, Vascular Aging and Stroke: Old Dogs, New Tricks? J Clin Med 2021; 10:jcm10194620. [PMID: 34640636 PMCID: PMC8509285 DOI: 10.3390/jcm10194620] [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] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/04/2021] [Accepted: 10/06/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Stroke remains a leading cause of death and disability throughout the world. It is well established that Diabetes Mellitus (DM) is a risk factor for stroke, while other risk factors include dyslipidaemia and hypertension. Given that the global prevalence of diabetes steadily increases, the need for adequate glycaemic control and prevention of DM-related cardiovascular events remains a challenge for the medical community. Therefore, a re-examination of the latest data related to this issue is of particular importance. OBJECTIVE This review aims to summarise the latest data on the relationship between DM and stroke, including epidemiology, risk factors, pathogenesis, prevention and biomarkers. METHODS For this purpose, comprehensive research was performed on the platforms PubMed, Google Scholar and EMBASE with a combination of the following keywords: diabetes mellitus, stroke, macrovascular complications, diabetic stroke, cardiovascular disease. CONCLUSIONS Much progress has been made in stroke in people with DM in terms of prevention and early diagnosis. In the field of prevention, the adaptation of the daily habits and the regulation of co-morbidity of individuals play a particularly important role. Simultaneously, the most significant revolution has been brought by the relatively new treatment options that offer protection to the cardiovascular system. Moreover, many prognostic and diagnostic biomarkers have been identified, paving the way for early and accurate diagnoses. However, to date, there are crucial points that remain controversial and need further clarification.
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Affiliation(s)
- Theano Penlioglou
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, 68132 Alexandroupolis, Greece;
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic Diseases Department, “Carol Davila” University of Medicine, 020021 Bucharest, Romania;
| | - Nikolaos Papanas
- Diabetes Centre, Second Department of Internal Medicine, Democritus University of Thrace, 68132 Alexandroupolis, Greece;
- Correspondence: ; Fax: +30-25513-51723
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Neuropeptide α-Melanocyte-Stimulating Hormone Promotes Neurological Recovery and Repairs Cerebral Ischemia/Reperfusion Injury in Type 1 Diabetes. Neurochem Res 2021; 47:394-408. [PMID: 34586586 DOI: 10.1007/s11064-021-03453-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 12/13/2022]
Abstract
Persons with type 1 diabetes have an increased risk of stroke compared with the general population. α-Melanocyte-stimulating hormone (α-MSH) is a neuropeptide that has protective effects against ischemia/reperfusion (I/R) induced organ damages. In this study, we aimed to investigate the neuroprotective role of this peptide on I/R induced brain damage after experimental stroke associated with hyperglycemia using C57BL/6J Ins2Akita/+ mice. Experimental stroke was induced by blocking the right middle cerebral artery for 2 h with reperfusion for 2 and 22 h, respectively using the intraluminal method. Animals were treated intraperitoneally with or without α-MSH at 1 h after ischemia and 1 h after reperfusion. Significantly higher survival rate and lower neurological scores were recorded in animals injected with α-MSH. Similarly, neuron death, glial cells activation as well as oxidative and nitrosative stress were significantly decreased in α-MSH treated group. Relative intensities of matrix metallopeptidases 9, cyclooxygenase 2 and nuclear factor-κB were significantly decreased while intensities of Akt, heme oxygenase (HO) 1, HO-2 and B-cell lymphoma 2 were significantly increased after α-MSH treatment. In addition, gene expressions of monocarboxylate transporter (MCT) 1, MCT-2 and activity-regulated cytoskeleton-associated protein were significantly higher in brain samples treated with α-MSH, suggesting this peptide may have role in neuron survival by an involvement of lactate metabolism. In conclusion, α-MSH is neuroprotective under hyperglycemic condition against I/R induced brain damage by its anti-inflammatory, anti-oxidative and anti-apoptotic properties. The use of α-MSH analogues may be potential therapeutic agents for diabetic stroke.
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Ylinen A, Hägg-Holmberg S, Eriksson MI, Forsblom C, Harjutsalo V, Putaala J, Groop PH, Thorn LM. The impact of parental risk factors on the risk of stroke in type 1 diabetes. Acta Diabetol 2021; 58:911-917. [PMID: 33721078 PMCID: PMC8187180 DOI: 10.1007/s00592-021-01694-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 02/23/2021] [Indexed: 11/18/2022]
Abstract
BACKGROUND Individuals with type 1 diabetes have a markedly increased risk of stroke. In the general population, genetic predisposition has been linked to increased risk of stroke, but this has not been assessed in type 1 diabetes. Our aim was, therefore, to study how parental risk factors affect the risk of stroke in individuals with type 1 diabetes. METHODS This study represents an observational follow-up of 4011 individuals from the Finnish Diabetic Nephropathy Study, mean age at baseline 37.6 ± 11.9 years. All strokes during follow-up were verified from medical records or death certificates. The strokes were classified as either ischemic or hemorrhagic. All individuals filled out questionnaires concerning their parents' medical history of hypertension, diabetes, stroke, and/or myocardial infarction. RESULTS During a median follow-up of 12.4 (10.9-14.2) years, 188 individuals (4.6%) were diagnosed with their first ever stroke; 134 were ischemic and 54 hemorrhagic. In Cox regression analysis, a history of maternal stroke increased the risk of hemorrhagic stroke, hazard ratio 2.86 (95% confidence interval 1.27-6.44, p = 0.011) after adjustment for sex, age, BMI, retinal photocoagulation, and diabetic kidney disease. There was, however, no association between maternal stroke and ischemic stroke. No other associations between parental risk factors and ischemic or hemorrhagic stroke were observed. CONCLUSION A history of maternal stroke increases the risk of hemorrhagic stroke in individuals with type 1 diabetes. Other parental risk factors seem to have limited impact on the risk of stroke.
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Affiliation(s)
- Anni Ylinen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Stefanie Hägg-Holmberg
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Marika I Eriksson
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- National Institute for Health and Welfare, Helsinki, Finland
| | - Jukka Putaala
- Helsinki University Hospital and University of Helsinki, Neurology, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia.
| | - Lena M Thorn
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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12
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Park SJ, Yang HK, Byun SJ, Park KH, Hwang JM. Risk of ischemic stroke after third, fourth, and sixth cranial nerve palsies in type 2 diabetes. J Diabetes 2019; 11:379-385. [PMID: 30251398 DOI: 10.1111/1753-0407.12859] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 09/05/2018] [Accepted: 09/18/2018] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND The aim of this study was to define the risk of ischemic stroke among newly diagnosed type 2 diabetes (T2D) patients who developed ocular motor cranial nerve (CN) palsies. METHODS From the National Health Insurance Service - National Sample Cohort database (2002-2013) of a random sample of 1 025 340 Koreans, patients with newly diagnosed T2D aged ≥20 years were included in the study. The incidence of ocular motor CN palsies was identified using diagnostic codes for third, fourth, and sixth CN palsies. To determine the effect of incident ocular motor CN palsy on subsequent ischemic stroke, covariate Cox regression was used (Model 1 included only ocular motor CN palsy as a time-varying covariate; Model 2 included ocular motor CN palsy and demographic information; Model 3 included all variables in Model 2 as well as comorbidity, concomitant medication, and the Charlson comorbidity index score). RESULTS Of 45 820 T2D patients, 75 developed ocular motor CN palsy and 1411 had ischemic stroke. Four patients experienced ischemic stroke after the development of ocular motor CN palsy. Incident ocular motor CN palsy was associated with the subsequent risk of ischemic stroke in Models 1, 2 and 3 (hazard ratios [95% confidence intervals] 3.74 [1.40-9.98], 3.33 [1.25-8.89], and 2.96 [1.11-7.92], respectively). Male sex, older age, and lower income were associated with an increased risk of ischemic stroke. Among confounders, hypertension, atrial fibrillation, and congestive heart failure were associated with the risk of ischemic stroke. CONCLUSIONS Physicians should pay more attention to manageable risk factors of ischemic stroke when diabetic patients suffer from ocular motor CN palsies.
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Affiliation(s)
- Sang Jun Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hee Kyung Yang
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Seong Jun Byun
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kyu Hyung Park
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jeong-Min Hwang
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
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13
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Pease A, Earnest A, Ranasinha S, Nanayakkara N, Liew D, Wischer N, Andrikopoulos S, Zoungas S. Burden of cardiovascular risk factors and disease among patients with type 1 diabetes: results of the Australian National Diabetes Audit (ANDA). Cardiovasc Diabetol 2018; 17:77. [PMID: 29859534 PMCID: PMC5984751 DOI: 10.1186/s12933-018-0726-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 05/26/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cardiovascular risk stratification is complex in type 1 diabetes. We hypothesised that traditional and diabetes-specific cardiovascular risk factors were prevalent and strongly associated with cardiovascular disease (CVD) among adults with type 1 diabetes attending Australian diabetes centres. METHODS De-identified, prospectively collected data from patients with type 1 diabetes aged ≥ 18 years in the 2015 Australian National Diabetes Audit were analysed. The burden of cardiovascular risk factors [age, sex, diabetes duration, glycated haemoglobin (HbA1c), blood pressure, lipid profile, body mass index, smoking status, retinopathy, renal function and albuminuria] and associations with CVD inclusive of stroke, myocardial infarction, coronary artery bypass graft surgery/angioplasty and peripheral vascular disease were assessed. Restricted cubic splines assessed for non-linearity of diabetes duration and likelihood ratio test assessed for interactions between age, diabetes duration, centre type and cardiovascular outcomes of interest. Discriminatory ability of multivariable models were assessed with area under the receiver operating characteristic (ROC) curves. RESULTS Data from 1169 patients were analysed. Mean (± SD) age and median diabetes duration was 40.0 (± 16.7) and 16.0 (8.0-27.0) years respectively. Cardiovascular risk factors were prevalent including hypertension (21.9%), dyslipidaemia (89.4%), overweight/obesity (56.4%), ever smoking (38.5%), albuminuria (31.1%), estimated glomerular filtration rate < 60 mL/min/1.73 m2 (10.3%) and HbA1c > 7.0% (53 mmol/mol) (81.0%). Older age, longer diabetes duration, smoking and antihypertensive therapy use were positively associated with CVD, while high density lipoprotein-cholesterol and diastolic blood pressure were negatively associated (p < 0.05). Association with CVD and diabetes duration remained constant until 20 years when a linear increase was noted. Longer diabetes duration also had the highest population attributable risk of 6.5% (95% CI 1.4, 11.6). Further, the models for CVD demonstrated good discriminatory ability (area under the ROC curve 0.88; 95% CI 0.84, 0.92). CONCLUSIONS Cardiovascular risk factors were prevalent and strongly associated with CVD among adults with type 1 diabetes attending Australian diabetes centres. Given the approximate J-shaped association between type 1 diabetes duration and CVD, the impact of cardiovascular risk stratification and management before and after 20 years duration needs to be further assessed longitudinally. Diabetes specific cardiovascular risk stratification tools incorporating diabetes duration should be an important consideration in future guideline development.
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Affiliation(s)
- Anthony Pease
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia.,Diabetes and Vascular Medicine Unit, Monash Health, Clayton, VIC, 3168, Australia
| | - Arul Earnest
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Sanjeeva Ranasinha
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Natalie Nanayakkara
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia.,Diabetes and Vascular Medicine Unit, Monash Health, Clayton, VIC, 3168, Australia
| | - Danny Liew
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Natalie Wischer
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia
| | - Sofianos Andrikopoulos
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia.,Department of Medicine, The University of Melbourne, Melbourne, VIC, 3010, Australia
| | - Sophia Zoungas
- School of Public Health and Preventive Medicine, Monash University, 5th Floor, The Alfred Centre, 99 Commercial Road, Melbourne, VIC, 3004, Australia. .,Diabetes and Vascular Medicine Unit, Monash Health, Clayton, VIC, 3168, Australia.
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14
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Carbonell M, Castelblanco E, Valldeperas X, Betriu À, Traveset A, Granado-Casas M, Hernández M, Vázquez F, Martín M, Rubinat E, Lecube A, Franch-Nadal J, Fernández E, Puig-Domingo M, Avogaro A, Alonso N, Mauricio D. Diabetic retinopathy is associated with the presence and burden of subclinical carotid atherosclerosis in type 1 diabetes. Cardiovasc Diabetol 2018; 17:66. [PMID: 29728117 PMCID: PMC5935933 DOI: 10.1186/s12933-018-0706-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Accepted: 04/18/2018] [Indexed: 02/07/2023] Open
Abstract
Background Cardiovascular (CV) disease due to atherosclerosis is a major cause of morbidity and mortality in adult patients with diabetes, either type 1 or type 2 diabetes. The aim of the study was to assess the association of the frequency and the burden of subclinical carotid atherosclerotic disease in patients with type 1 diabetes according to the presence and severity of diabetic retinopathy (DR). Methods A cross-sectional study was conducted in 340 patients with type 1 diabetes (41.5% with DR), and in 304 non-diabetic individuals. All participants were free from previous CV disease and chronic kidney disease (CKD). B-mode carotid ultrasound imaging was performed in all the study subjects. Patients with type 1 diabetes underwent a full eye examination, and DR patients were divided into two groups: mild disease and advanced disease. Results In the group of patients with type 1 diabetes, the percentage of patients with carotid plaques was higher in those with DR compared with those without DR (44.7% vs. 24.1%, p < 0.001). Patients with DR also presented a higher incidence of ≥ 2 carotid plaques (25.5% vs. 11.1%, p < 0.001). Apart from other traditional cardiovascular risk factors, the presence of advanced stages of DR was independently associated with the presence (p = 0.044) and the burden (≥ 2 carotid plaques; p = 0.009) of subclinical carotid atherosclerosis. Conclusions In patients with type 1 diabetes without previous CV disease or established CKD, the presence of advanced stages of DR is associated with a higher atherosclerotic burden in the carotid arteries. The presence of DR identifies patients at risk for carotid atherosclerotic disease. Electronic supplementary material The online version of this article (10.1186/s12933-018-0706-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Marc Carbonell
- Department of Ophthalmology, University Hospital Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, Barcelona Autonomous University (UAB), Barcelona, Spain.,Department of Surgery, Barcelona Autonomous University (UAB), Barcelona, Spain
| | - Esmeralda Castelblanco
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain.,Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain
| | - Xavier Valldeperas
- Department of Ophthalmology, University Hospital Germans Trias i Pujol, Badalona, Spain.,Department of Medicine, Barcelona Autonomous University (UAB), Barcelona, Spain.,Department of Surgery, Barcelona Autonomous University (UAB), Barcelona, Spain
| | - Àngels Betriu
- Biomedical Research Institute of Lleida, Lleida, Spain
| | - Alícia Traveset
- Department of Ophthalmology, University Hospital Arnau de Vilanova, Lleida, Spain
| | - Minerva Granado-Casas
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain.,Biomedical Research Institute of Lleida, Lleida, Spain
| | - Marta Hernández
- Biomedical Research Institute of Lleida, Lleida, Spain.,Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, Lleida, Spain
| | - Federico Vázquez
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain
| | - Mariona Martín
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain
| | | | - Albert Lecube
- Biomedical Research Institute of Lleida, Lleida, Spain.,Department of Endocrinology and Nutrition, University Hospital Arnau de Vilanova, Lleida, Spain
| | - Josep Franch-Nadal
- Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.,Primary Health Care Center Raval Sud, Gerència d'Atenció Primaria, Institut Català de la Salut, Barcelona, Spain
| | | | - Manel Puig-Domingo
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain.,Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain.,Department of Medicine, Barcelona Autonomous University (UAB), Barcelona, Spain
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padua, Italy
| | - Núria Alonso
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain. .,Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain. .,Biomedical Research Institute of Lleida, Lleida, Spain. .,Department of Medicine, Barcelona Autonomous University (UAB), Barcelona, Spain.
| | - Dídac Mauricio
- Department of Endocrinology and Nutrition, University Hospital and Health Science Research Institute Germans Trias i Pujol, Carretera Canyet S/N, 08916, Badalona, Spain. .,Center for Biomedical Research on Diabetes and Associated Metabolic Diseases (CIBERDEM), Barcelona, Spain. .,Biomedical Research Institute of Lleida, Lleida, Spain. .,Department of Medicine, Barcelona Autonomous University (UAB), Barcelona, Spain.
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15
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Hägg-Holmberg S, Thorn LM, Forsblom CM, Gordin D, Elonen N, Harjutsalo V, Liebkind R, Putaala J, Tatlisumak T, Groop PH. Prognosis and Its Predictors After Incident Stroke in Patients With Type 1 Diabetes. Diabetes Care 2017; 40:1394-1400. [PMID: 28811283 DOI: 10.2337/dc17-0681] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 07/09/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Although patients with type 1 diabetes have a poor prognosis after a stroke, predictors of survival after an incident stroke in these patients are poorly studied. RESEARCH DESIGN AND METHODS In this observational study, a total of 144 patients of 4,083 with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study suffered an incident stroke in 1997-2010, and were followed for a mean 3.4 ± 3.1 years after the stroke. Information was recorded on hard cardiovascular events and death as a result of cardiovascular or diabetes-related cause, collectively referred to as vascular composite end point. Information was collected from medical records, death certificates, and the National Care Register of Health Care. Predictors at the time of the incident stroke were studied for the end points. RESULTS During follow-up, 104 (72%) patients suffered a vascular composite end point. Of these, 33 (32%) had a recurrent stroke, 33 (32%) a hard cardiovascular event, and 76 (53%) died of cardiovascular or diabetes-related causes, with an overall 1-year survival of 76% and 5-year survival of 58%. The predictors of a vascular composite end point were hemorrhagic stroke subtype (hazard ratio 2.03 [95% CI 1.29-3.19]), as well as chronic kidney disease stage 2 (2.48 [1.17-5.24]), stage 3 (3.04 [1.54-6.04]), stage 4 (3.95 [1.72-9.04]), and stage 5 (6.71 [3.14-14.34]). All-cause mortality increased with deteriorating kidney function. CONCLUSIONS Patients with type 1 diabetes with an incident stroke have a poor cardiovascular prognosis and a high risk of all-cause mortality. In particular, hemorrhagic stroke subtype and progression of diabetic kidney disease conveys worse outcome.
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Affiliation(s)
- Stefanie Hägg-Holmberg
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Lena M Thorn
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Carol M Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Daniel Gordin
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Nina Elonen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Valma Harjutsalo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - Ron Liebkind
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Jukka Putaala
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
| | - Turgut Tatlisumak
- Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.,Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.,Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland .,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia
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16
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Ståhl CH, Lind M, Svensson AM, Gudbjörnsdottir S, Mårtensson A, Rosengren A. Glycaemic control and excess risk of ischaemic and haemorrhagic stroke in patients with type 1 diabetes: a cohort study of 33 453 patients. J Intern Med 2017; 281:261-272. [PMID: 27925333 DOI: 10.1111/joim.12572] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To estimate the excess risk of stroke in relation to glycaemic control in patients with type 1 diabetes. METHODS In this prospective, matched cohort study, we identified patients with type 1 diabetes, aged ≥18 years, who were registered in the Swedish National Diabetes Register from 1998-2011 and five control subjects for each case from the general population, matched for age, sex and county of residence. The risks of all strokes, ischaemic stroke and haemorrhagic stroke were estimated using Cox hazard regression. RESULTS Of 33 453 type 1 diabetes patients [mean age, 35.5 (SD 14.4) years; mean follow-up, 7.9 (SD 4.3) years; and mean diabetes duration, 20.2 years (SD 14.6)], 762 (2.3%) were diagnosed with stroke compared with 1122 (0.7%) of 159 924 control subjects [mean follow-up, 8.2 (SD 4.3) years]. The overall multiple-adjusted hazard ratios (HRs) for type 1 diabetes patients versus control subjects were 3.29 (95% CI: 2.96-3.66) and 2.49 (95% CI: 1.96-3.16) for ischaemic and haemorrhagic stroke, respectively. The risk of ischaemic and haemorrhagic stroke incrementally increased with increasing HbA1c; the risk of ischaemic stroke was significantly increased with HbA1c within target [≤6.9% (≤52 mmol mol-1 )] [multiple-adjusted HR 1.89 (95% CI: 1.44-2.47)]. For HbA1c ≥9.7% (≥83 mmol mol-1 ), there was a markedly increased risk of both ischaemic and haemorrhagic stroke, with multiple-adjusted HRs of 7.94 (95% CI: 6.29-10.03) and 8.17 (95% CI 5.00-13.35), respectively. CONCLUSIONS Individuals with type 1 diabetes have an increased risk of ischaemic and haemorrhagic stroke, increasing markedly with poor glycaemic control.
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Affiliation(s)
- C Hedén Ståhl
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - M Lind
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.,Department of Medicine, NU-Hospital Organization, Uddevalla, Sweden
| | - A-M Svensson
- Center of Registers in Region Västra Götaland, Gothenburg, Sweden
| | | | | | - A Rosengren
- Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
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17
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Shukla V, Shakya AK, Perez-Pinzon MA, Dave KR. Cerebral ischemic damage in diabetes: an inflammatory perspective. J Neuroinflammation 2017; 14:21. [PMID: 28115020 PMCID: PMC5260103 DOI: 10.1186/s12974-016-0774-5] [Citation(s) in RCA: 125] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 12/07/2016] [Indexed: 12/16/2022] Open
Abstract
Stroke is one of the leading causes of death worldwide. A strong inflammatory response characterized by activation and release of cytokines, chemokines, adhesion molecules, and proteolytic enzymes contributes to brain damage following stroke. Stroke outcomes are worse among diabetics, resulting in increased mortality and disabilities. Diabetes involves chronic inflammation manifested by reactive oxygen species generation, expression of proinflammatory cytokines, and activation/expression of other inflammatory mediators. It appears that increased proinflammatory processes due to diabetes are further accelerated after cerebral ischemia, leading to increased ischemic damage. Hypoglycemia is an intrinsic side effect owing to glucose-lowering therapy in diabetics, and is known to induce proinflammatory changes as well as exacerbate cerebral damage in experimental stroke. Here, we present a review of available literature on the contribution of neuroinflammation to increased cerebral ischemic damage in diabetics. We also describe the role of hypoglycemia in neuroinflammation and cerebral ischemic damage in diabetics. Understanding the role of neuroinflammatory mechanisms in worsening stroke outcome in diabetics may help limit ischemic brain injury and improve clinical outcomes.
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Affiliation(s)
- Vibha Shukla
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA.,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA
| | - Akhalesh Kumar Shakya
- Present address: Department of Microbiology and Immunology, and Center for Molecular and Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130, USA
| | - Miguel A Perez-Pinzon
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA.,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA.,Neuroscience Program, University of Miami School of Medicine, Miami, FL, 33136, USA
| | - Kunjan R Dave
- Cerebral Vascular Disease Research Laboratories, University of Miami School of Medicine, Miami, FL, 33136, USA. .,Department of Neurology (D4-5), University of Miami Miller School of Medicine, 1420 NW 9th Ave, NRB/203E, Miami, FL, 33136, USA. .,Neuroscience Program, University of Miami School of Medicine, Miami, FL, 33136, USA.
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18
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Nyström T, Holzmann MJ, Sartipy U. Long-Term Risk of Stroke in Patients With Type 1 and Type 2 Diabetes Following Coronary Artery Bypass Grafting. J Am Heart Assoc 2015; 4:e002411. [PMID: 26553216 PMCID: PMC4845229 DOI: 10.1161/jaha.115.002411] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/17/2015] [Indexed: 12/02/2022]
Abstract
BACKGROUND We performed a nationwide population-based cohort study to investigate the long-term risk of stroke after coronary artery bypass grafting in patients with type 1 and type 2 diabetes. METHODS AND RESULTS All patients who underwent primary coronary artery bypass grafting in Sweden from 2000 through 2011 were included from the SWEDEHEART register. We excluded patients with prior stroke, and patients who had a stroke or died within 30 days of surgery. The National Diabetes Register was used to identify patients with type 1 and type 2 diabetes. Incident stroke (ischemic and hemorrhagic), and all-cause mortality was obtained by record linkage with the National Patient Register and the Cause of Death register. We used multivariable Cox regression to estimate the risk of stroke in relation to type of diabetes. A total of 53 820 patients (type 1 diabetes [n=714], type 2 diabetes [n=10 054], no diabetes [n=43 052]) were included. During a mean follow-up of 7.4 years (398 337 person-years), in total, 8.0% (n=4296) of the patients had a stroke: 7.3% (n=52) in patients with type 1 diabetes, 9.1% (n=915) in patients with type 2 diabetes, and 7.7% (n=3329) in patients with no diabetes. The multivariable adjusted hazard ratio (95% CI) for all stroke was 1.59 (1.20-2.11) in type 1 diabetes, and 1.32 (1.23-1.43) in type 2 diabetes. CONCLUSIONS The long-term risk for stroke after coronary artery bypass grafting was increased in patients with type 1 and type 2 diabetes, compared to patients with no diabetes.
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Affiliation(s)
- Thomas Nyström
- Department of Clinical Science and ResearchKarolinska InstitutetStockholmSweden
- Division of Internal MedicineSödersjukhusetStockholmSweden
| | - Martin J. Holzmann
- Department of Internal MedicineKarolinska InstitutetStockholmSweden
- Department of Emergency MedicineKarolinska University HospitalStockholmSweden
| | - Ulrik Sartipy
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Cardiothoracic Surgery and AnesthesiologyKarolinska University HospitalStockholmSweden
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19
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Huxley RR, Peters SAE, Mishra GD, Woodward M. Risk of all-cause mortality and vascular events in women versus men with type 1 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2015; 3:198-206. [PMID: 25660575 DOI: 10.1016/s2213-8587(14)70248-7] [Citation(s) in RCA: 250] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Studies have suggested sex differences in the mortality rate associated with type 1 diabetes. We did a meta-analysis to provide reliable estimates of any sex differences in the effect of type 1 diabetes on risk of all-cause mortality and cause-specific outcomes. METHODS We systematically searched PubMed for studies published between Jan 1, 1966, and Nov 26, 2014. Selected studies reported sex-specific estimates of the standardised mortality ratio (SMR) or hazard ratios associated with type 1 diabetes, either for all-cause mortality or cause-specific outcomes. We used random effects meta-analyses with inverse variance weighting to obtain sex-specific SMRs and their pooled ratio (women to men) for all-cause mortality, for mortality from cardiovascular disease, renal disease, cancer, the combined outcome of accident and suicide, and from incident coronary heart disease and stroke associated with type 1 diabetes. FINDINGS Data from 26 studies including 214 114 individuals and 15 273 events were included. The pooled women-to-men ratio of the SMR for all-cause mortality was 1·37 (95% CI 1·21-1·56), for incident stroke 1·37 (1·03-1·81), for fatal renal disease 1·44 (1·02-2·05), and for fatal cardiovascular diseases 1·86 (1·62-2·15). For incident coronary heart disease the sex difference was more extreme; the pooled women-to-men ratio of the SMR was 2·54 (95% CI 1·80-3·60). No evidence suggested a sex difference for mortality associated with type 1 diabetes from cancer, or accident and suicide. INTERPRETATION Women with type 1 diabetes have a roughly 40% greater excess risk of all-cause mortality, and twice the excess risk of fatal and nonfatal vascular events, compared with men with type 1 diabetes. FUNDING None.
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Affiliation(s)
- Rachel R Huxley
- School of Public Health, University of Queensland, Brisbane, QLD, Australia; The George Institute for Global Health, University of Sydney, Sydney, Australia.
| | - Sanne A E Peters
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Gita D Mishra
- School of Public Health, University of Queensland, Brisbane, QLD, Australia
| | - Mark Woodward
- The George Institute for Global Health, University of Sydney, Sydney, Australia; The George Institute for Global Health, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
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Hägg S, Thorn LM, Forsblom CM, Gordin D, Saraheimo M, Tolonen N, Wadén J, Liebkind R, Putaala J, Tatlisumak T, Groop PH. Different risk factor profiles for ischemic and hemorrhagic stroke in type 1 diabetes mellitus. Stroke 2014; 45:2558-62. [PMID: 25061078 DOI: 10.1161/strokeaha.114.005724] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND PURPOSE Despite the fact that patients with type 1 diabetes mellitus have a markedly increased risk of experiencing a stroke, independent risk factors for stroke and its subtypes in these patients have remained unclear. METHODS A total of 4083 patients with type 1 diabetes mellitus from the Finnish Diabetic Nephropathy (FinnDiane) Study, without a history of stroke at baseline, were included. Strokes were classified based on medical files and brain imaging. At baseline, mean age was 37.4±11.8 years, duration of diabetes mellitus was 20.0 (11.0-30.0) years, and 51% were men. During 9.0±2.7 years (36 680 patient-years) of follow-up, 105 patients experienced an ischemic stroke and 44 a hemorrhagic stroke. Cox proportional hazards analyses were performed to determine independent risk factors. RESULTS Independent risk factors for ischemic stroke were duration of diabetes mellitus, presence of diabetic nephropathy, higher hemoglobin A1c, higher systolic blood pressure, insulin resistance, and history of smoking, whereas sex, lipids, high-sensitivity C-reactive protein, and the metabolic syndrome were not associated with an increased risk. Diabetic nephropathy, severe diabetic retinopathy, higher systolic blood pressure, and lower body mass index were independently associated with hemorrhagic stroke. CONCLUSIONS The risk factor profile for ischemic stroke seems partly different from that of hemorrhagic stroke in patients with type 1 diabetes mellitus.
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Affiliation(s)
- Stefanie Hägg
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Lena M Thorn
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Carol M Forsblom
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Daniel Gordin
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Markku Saraheimo
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Nina Tolonen
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Johan Wadén
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Ron Liebkind
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Jukka Putaala
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Turgut Tatlisumak
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.)
| | - Per-Henrik Groop
- From the Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); Division of Nephrology, Department of Medicine (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.) and Department of Neurology (R.L., J.P., T.T.), Helsinki University Central Hospital, Helsinki, Finland; Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland (S.H., L.M.T., C.M.F., D.G., M.S., N.T., J.W., P.-H.G.); and Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia (P.-H.G.).
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Distiller LA. Why do some patients with type 1 diabetes live so long? World J Diabetes 2014; 5:282-287. [PMID: 24936249 PMCID: PMC4058732 DOI: 10.4239/wjd.v5.i3.282] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 03/05/2014] [Accepted: 04/09/2014] [Indexed: 02/05/2023] Open
Abstract
While the lifespan of people with type 1 diabetes has increased progressively since the advent of insulin therapy, these patients still experience premature mortality, primarily from cardiovascular disease (CVD). However, a subgroup of those with type 1 diabetes survives well into old age without significant morbidity. It is the purpose of this review to explore the factors which may help in identifying these patients. It might be expected that hyperglycaemia plays a major role in explaining the increased incidence of CVD and mortality of these individuals. However, while a number of publications have associated poor long term glycaemic control with an increase in both all-cause mortality and CVD in those with type 1 diabetes, it is apparent that good glycaemic control alone cannot explain why some patients with type 1 diabetes avoid fatal CVD events. Lipid disorders may occur in those with type 1 diabetes, but the occurrence of elevated high-density lipoprotein-cholesterol is positively associated with longevity in this population. Non-renal hypertension, by itself is a significant risk factor for CVD but if adequately treated does not appear to mitigate against longevity. However, the presence of nephropathy is a major risk factor and its absence after 15-20 years of diabetes appears to be a marker of long-term survival. One of the major factors linked with long-term survival is the absence of features of the metabolic syndrome and more specifically the presence of insulin sensitivity. Genetic factors also play a role, with a family history of longevity and an absence of type 2 diabetes and hypertension in the family being important considerations. There is thus a complex interaction between multiple risk factors in determining which patients with type 1 diabetes are likely to live into older age. However, these patients can often be identified clinically based on a combination of factors as outlined above.
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Kim E, Tolhurst AT, Cho S. Deregulation of inflammatory response in the diabetic condition is associated with increased ischemic brain injury. J Neuroinflammation 2014; 11:83. [PMID: 24886035 PMCID: PMC4017808 DOI: 10.1186/1742-2094-11-83] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 03/26/2014] [Indexed: 01/04/2023] Open
Abstract
Background Although elicited inflammation contributes to tissue injury, a certain level of inflammation is necessary for subsequent tissue repair/remodeling. Diabetes, a chronic low-grade inflammatory state, is a predisposing risk factor for stroke. The condition is associated with delayed wound healing, presumably due to disrupted inflammatory responses. With inclusion of the diabetic condition in an experimental animal model of stroke, this study investigates whether the condition alters inflammatory response and influences stroke-induced brain injury. Methods C57BL/6 mice were fed a diabetic diet (DD) for 8 weeks to induce an experimental diabetic condition or a normal diet (ND) for the same duration. Gene expression of inflammatory factors including monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), CCR2, and CD36 was assessed in the peripheral immune cells and brains of normal and diabetic mice before and after focal cerebral ischemia. The expression of these factors was also determined in lipopolysaccharide (LPS)-treated cultured normal and diabetic macrophages. Ischemic outcome was assessed in these mice at 3 days post-ischemia. Results DD intervention in mice resulted in obesity and elevated insulin and glucose level in the blood. The peritoneal immune cells from the diabetic mice showed higher MCP-1 mRNA levels before and after stroke. Compared to normal mice, diabetic mice showed reduced MCP-1, IL-6, and CCR2 gene expression in the brain at 6 h post-ischemia. LPS-stimulated inflammatory responses were also reduced in the diabetic macrophages. The diabetic mice showed larger infarct size and percent swelling. Conclusions These results showed that diabetic conditions deregulate acute inflammatory response and that the condition is associated with increased stroke-induced injury. The study suggests that interventions aimed at restoring appropriate inflammatory response in peripheral immune cells/macrophages may be beneficial in reducing stroke-induced brain injury in subjects with chronic inflammatory conditions.
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Affiliation(s)
| | | | - Sunghee Cho
- Burke-Cornell Medical Research Institute, White Plains, NY 10605, USA.
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Woerdeman J, van Duinkerken E, Wattjes MP, Barkhof F, Snoek FJ, Moll AC, Klein M, de Boer MP, Ijzerman RG, Serné EH, Diamant M. Proliferative retinopathy in type 1 diabetes is associated with cerebral microbleeds, which is part of generalized microangiopathy. Diabetes Care 2014; 37:1165-8. [PMID: 24319122 DOI: 10.2337/dc13-1586] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We investigated whether proliferative diabetic retinopathy in type 1 diabetic patients can be generalized to cerebral small vessel disease and whether it is associated with impaired peripheral microvascular function. RESEARCH DESIGN AND METHODS Thirty-three patients with proliferative diabetic retinopathy (PDR+), 34 patients without proliferative diabetic retinopathy, and 33 controls underwent magnetic resonance imaging to assess cerebral microangiopathy (cerebral microbleeds) and ischemic damage (white matter hyperintensities and lacunes). Peripheral microvascular function, i.e., skin capillary density and capillary recruitment, was assessed by capillary microscopy. RESULTS Cerebral microbleeds, but not ischemic damage, were more prevalent in PDR+ patients versus the other groups (P < 0.05). A trend was found across groups for the lowest baseline capillary density in PDR+ patients (P for trend = 0.05). In individuals with microbleeds, capillary recruitment was impaired compared with those without microbleeds (P = 0.04). CONCLUSIONS In PDR+ patients, cerebral microbleed prevalence was higher and seems part of generalized microangiopathy that may affect the skin and the brain.
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Hägg S, Thorn LM, Putaala J, Liebkind R, Harjutsalo V, Forsblom CM, Gordin D, Tatlisumak T, Groop PH. Incidence of stroke according to presence of diabetic nephropathy and severe diabetic retinopathy in patients with type 1 diabetes. Diabetes Care 2013; 36:4140-6. [PMID: 24101700 PMCID: PMC3836162 DOI: 10.2337/dc13-0669] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Type 1 diabetes is associated with a markedly increased risk of stroke, but only a few studies on the incidence of stroke in type 1 diabetes exist. Therefore, we assessed the incidence of stroke in patients with type 1 diabetes and studied the impact of diabetic nephropathy (DN) and severe diabetic retinopathy (SDR) on this risk. RESEARCH DESIGN AND METHODS We studied 4,083 patients with type 1 diabetes from the Finnish Diabetic Nephropathy Study. Mean age was 37.4 ± 11.8 years, duration of diabetes was 21.6 ± 12.1 years, and 52% were men. Strokes were identified from medical records, death certificates, and the National Hospital Discharge Register and classified based on medical files and brain images. RESULTS During 36,680 person-years of follow-up, 149 (4%) patients suffered an incident stroke (105 infarctions and 44 hemorrhages). Of the infarctions, 58 (55%) were lacunar. The incidence of stroke, cerebral infarction, and cerebral hemorrhage was 406 (95% CI 344-477), 286 (234-347), and 120 (87-161) per 100,000 person-years, respectively. In an adjusted analysis, microalbuminuria increased the risk of stroke with a hazard ratio (HR) of 3.2 (1.9-5.6), macroalbuminuria 4.9 (2.9-8.2), and end-stage renal disease 7.5 (4.2-13.3), and SDR increased the risk with an HR of 3.0 (1.9-4.5). The risk of cerebral infarction, cerebral hemorrhage, and lacunar infarction increased in a similar manner. The proportion of lacunar versus nonlacunar infarction did not change across DN groups. CONCLUSIONS The presence of SDR and DN, independently, increases the risk of stroke, cerebral infarction, and cerebral hemorrhage in patients with type 1 diabetes.
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Secrest AM, Prince CT, Costacou T, Miller RG, Orchard TJ. Predictors of and survival after incident stroke in type 1 diabetes. Diab Vasc Dis Res 2013; 10:3-10. [PMID: 22535586 PMCID: PMC3635676 DOI: 10.1177/1479164112441006] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Few studies have examined stroke risk in type 1 diabetes mellitus (T1DM). Stroke incidence, predictors, and survival were thus explored in this study. Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants (n = 658) with childhood-onset T1DM were followed biennially for 18 years. Baseline (1986-1988) mean age and diabetes duration were 28 and 19 years respectively. Stroke incidence and type was determined via survey or physician interview and, when possible, confirmed with medical or autopsy records. During follow-up, 31 (4.7%) strokes occurred (21 ischaemic, 8 haemorrhagic, 2 unclassified) in participants of mean age = 40.2 years (range 23-60). In exploratory multivariable Cox modelling, diabetes duration, systolic blood pressure (SBP), non-high density lipoprotein cholesterol (non-HDLc), white blood cells (WBC), and pulse significantly predicted ischaemic stroke. Adding overt nephropathy (ON) (hazard ratio = 4.4, 95% CI, 1.5-12.4) to the model replaced SBP. Participant survival after stroke was 80.6%, 45.2%, and 9.6% at 1, 5, and 10 years, respectively, and significantly worse after haemorrhagic stroke (p = 0.03). These risk factors merit careful evaluation and management to prevent stroke in T1DM, which occurs at least 20 years earlier than in the general population.
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Affiliation(s)
| | | | | | | | - Trevor J. Orchard
- Corresponding Author: Dr. Trevor J. Orchard, MD, 3512 Fifth Avenue, 2 Floor, Pittsburgh, PA 15213, Phone: 412-383-1032, Fax: 412-383-1020,
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Ergul A, Kelly-Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: focus on stroke. Endocr Metab Immune Disord Drug Targets 2012; 12:148-58. [PMID: 22236022 DOI: 10.2174/187153012800493477] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2011] [Accepted: 09/27/2011] [Indexed: 12/18/2022]
Abstract
Cerebrovascular complications make diabetic patients 2-6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature.
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Affiliation(s)
- Adviye Ergul
- Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA 30912, USA
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Abstract
Diabetic men have benefited in the last 30 years from a significant improvement in total and cardiovascular mortality, whereas diabetic women have had no improvement at all. Moreover, recent research focused on the role of sex hormones in glucose homeostasis, and might account for different pathophysiologic mechanisms in the development of diabetes-related complications. Thus, care of diabetic women is a challenge that requires particular attention. The available data regarding gender-specific care of diabetes mellitus are uneven, rich in some domains but very poor in others. The large prospective trials performed in the last 20 years have assumed that the natural history of diabetes mellitus in men and women, as well as the efficiency of glucose-lowering therapies and management of hyperglycemic-related complications, could be attributable without distinction to men and women. We propose in this paper to analyze the published medical literature according to the specific management of diabetes mellitus in women, and to try to distinguish some particular features. We found important distinctions between diabetic men and women regarding the patterns of abnormalities of glucose regulation, epidemiology, development of diabetes-related complications, ischemic heart disease, morbidity and mortality, impact of cardiovascular risk factors, development of the metabolic syndrome, depression and osteoporosis, as well as the impact of lifestyle modifications or primary and secondary preventions on cardiovascular risk factors, and finally medical therapeutics. Moreover, special considerations were given to some particular aspects of the medical life in diabetic women, such as the features of gestational diabetes mellitus and the management of pregnancy in pregestational diabetic women, use of contraception, hormone-replacement therapy and polycystic ovary syndrome.
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Affiliation(s)
- Auryan Szalat
- Hadassah Hebrew University Hospital, Internal Medicine, Endocrinology and Metabolism, Jerusalem, Israel.
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Vargas R, Rincón J, Pedreañez A, Viera N, Hernández-Fonseca JP, Peña C, Mosquera J. Role of angiotensin II in the brain inflammatory events during experimental diabetes in rats. Brain Res 2012; 1453:64-76. [PMID: 22464881 DOI: 10.1016/j.brainres.2012.03.021] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Revised: 12/27/2011] [Accepted: 03/08/2012] [Indexed: 01/17/2023]
Abstract
Hyperglycemia during diabetes is one of the causes of encephalopathy. However, diabetes causes chronic inflammatory complications and among them is peripheral neuropathy. Since, diabetes is one of the major risk factors for cerebrovascular disease, inflammatory process could take place in central nervous system (CNS). To test that hypothesis, experiments to determine inflammatory events in CNS during streptozotocin-induced diabetes were performed. Diabetes was induced by intravenous injection of streptozotocin (STZ). Brain angiotensin II (Ang II), monocyte/macrophage (ED-1 positive cells), CD8, the intercellular adhesion molecule-1 (ICAM-1), the lymphocyte function-associated antigen-1 (LFA-1) and superoxide anion were determined by hystochemical and immunohistochemical methods. Nitric oxide (NO), malondialdehyde (MDA) and catalase activity were measured in brain homogenates by enzymatic and biochemical methods. This research showed increased expressions of Ang II, ICAM-1, LFA-1 and CD8 positive cells in diverse zones of cerebrum and cerebellum of diabetic rats (week 8). Treatment of diabetic animals with losartan or enalapril reduced the expression of those molecules. Values of lipid peroxidation, nitrite content and superoxide anion expression remained similar to control rats. Only decreased activity of catalase was observed in diabetic animals, but losartan or enalapril failed to modify catalase activity. This study suggests the presence of Ang II-mediated brain inflammatory events in diabetes probably mediated by AT1 receptors.
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Affiliation(s)
- Renata Vargas
- Instituto de Investigaciones Clínicas "Dr. Américo Negrette", Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
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Howells DW, Porritt MJ, Rewell SSJ, O'Collins V, Sena ES, van der Worp HB, Traystman RJ, Macleod MR. Different strokes for different folks: the rich diversity of animal models of focal cerebral ischemia. J Cereb Blood Flow Metab 2010; 30:1412-31. [PMID: 20485296 PMCID: PMC2949237 DOI: 10.1038/jcbfm.2010.66] [Citation(s) in RCA: 223] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Revised: 04/08/2010] [Accepted: 04/09/2010] [Indexed: 11/08/2022]
Abstract
No single animal model is able to encompass all of the variables known to affect human ischemic stroke. This review highlights the major strengths and weaknesses of the most commonly used animal models of acute ischemic stroke in the context of matching model and experimental aim. Particular emphasis is placed on the relationships between outcome and underlying vascular variability, physiologic control, and use of models of comorbidity. The aim is to provide, for novice and expert alike, an overview of the key controllable determinants of experimental stroke outcome to help ensure the most effective application of animal models to translational research.
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Affiliation(s)
- David W Howells
- National Stroke Research Institute and University of Melbourne Department of Medicine, Austin Health, Melbourne, Victoria, Australia.
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Vigili de Kreutzenberg S, Tiengo A, Avogaro A. Cerebrovascular disease in diabetes mellitus: the role of carotid intima-media thickness. Nutr Metab Cardiovasc Dis 2009; 19:667-673. [PMID: 19500958 DOI: 10.1016/j.numecd.2009.03.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2008] [Revised: 01/14/2009] [Accepted: 03/17/2009] [Indexed: 10/20/2022]
Abstract
BACKGROUND AND PURPOSE Cerebrovascular disease in diabetes appears to be less considered than coronary and peripheral disease, the reason being the intrinsic difficulty in finding available diagnostic tools for its early identification. Among these, carotid artery intima-media thickness (cIMT) represents the simplest measurable parameter for pre-atherosclerotic lesions in extra-cranic arteries. METHODS The role of cIMT as a surrogate marker of cerebral atherosclerosis and predictor of stroke, its relationship to microangiopathy and chronic inflammation, along with its role as an outcome parameter in anti-hyperglycemic therapeutical intervention trials in type 2 and 1 diabetes mellitus are discussed in this paper. RESULTS AND CONCLUSIONS Carotid IMT is increased in diabetes. It is an independent predictor of stroke, in particular of the ischemic subtype, and of stroke recurrence in diabetic, as well as in non-diabetic populations. A possible role of cIMT as a predictor of microangiopathy has also been suggested, but it needs further investigation. A weak association with chronic inflammation has been demonstrated in diabetic patients. Carotid IMT has been successfully employed as an outcome parameter for several anti-hyperglycemic therapeutic trials. However data on cIMT as a predictor of cerebrovascular disease are scarce in diabetic patients, particularly in type 1 diabetes, and more studies are needed to define the risk of cerebrovascular disease in diabetic patients.
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Affiliation(s)
- S Vigili de Kreutzenberg
- Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy.
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Szalat A, Raz I. Gender-specific care of diabetes mellitus: particular considerations in the management of diabetic women. Diabetes Obes Metab 2008; 10:1135-56. [PMID: 18494812 DOI: 10.1111/j.1463-1326.2008.00896.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
In the past 30 years, the all-cause mortality and cardiovascular mortality rates for women with diabetes mellitus (DM), in contrast to men, have not declined. Furthermore, the difference between all-cause mortality rates in women with DM and those without DM has more than doubled. This urgently needs addressing. This review will analyse published medical literature relating to the specific management of DM in women and try to identify areas where gender affects care. We have identified specific gender differences in the pathophysiology of glucose homeostasis disorder, diabetes-related complications and any female gender-specific features of women with diabetes, such as contraception and the menopause. These gender-specific features of DM may offer a route to improved care for women and new therapeutic possibilities.
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Affiliation(s)
- Auryan Szalat
- Department of Endocrinology and Metabolism, Hadassah Hebrew University Hospital, Jerusalem, Israel.
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Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, Gunderson EP, Herman WH, Hoffman LD, Inturrisi M, Jovanovic LB, Kjos SI, Knopp RH, Montoro MN, Ogata ES, Paramsothy P, Reader DM, Rosenn BM, Thomas AM, Kirkman MS. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 2008; 31:1060-79. [PMID: 18445730 PMCID: PMC2930883 DOI: 10.2337/dc08-9020] [Citation(s) in RCA: 255] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- John L Kitzmiller
- Division of Maternal-Fetal Medicine, Santa Clara Valley Medical Center, San Jose, California 95128, USA.
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Affiliation(s)
- George Howard
- Department of Biostatistics, UAB School of Public Health, Birmingham, AL 35294-0022, USA.
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Bibliography. Current world literature. Diabetes and the endocrine pancreas II. Curr Opin Endocrinol Diabetes Obes 2007; 14:329-57. [PMID: 17940461 DOI: 10.1097/med.0b013e3282c3a898] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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