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Richardson S, Marshall J, Rendeiro C. The role of cocoa flavanols in modulating peripheral and cerebral microvascular function in healthy individuals and populations at-risk of cardiovascular disease: a systematic review. Nutr J 2025; 24:57. [PMID: 40217225 PMCID: PMC11992872 DOI: 10.1186/s12937-025-01121-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 03/31/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Cocoa flavanols (CFs) are polyphenolic molecules with proposed cardioprotective effects. Whilst extensive evidence supports their ability to ameliorate vasodilator responses within conduit vessels, their actions in the microvasculature are less clear. This systematic review of the literature aimed to determine whether CF interventions lead to improvements in microvascular vasodilator responses in healthy populations and those with increased cardiovascular disease risk. METHODS Database searches were conducted up to September 2023 using Medline, Embase, Pubmed and Web of Science Core Collection to identify randomised, placebo-controlled, human studies investigating the effect of CF interventions on the microvasculature (at rest and vasodilator responses). All studies were assessed for risk of-bias according to Cochrane Collaboration recommendations for randomised-controlled trials, data were extracted from studies and findings collated by vote-counting. RESULTS Searches identified 511 unique articles for screening, of which 19 were selected for data extraction. Vasodilator responses were enhanced in 85.7% (80.4-91.0%, p = 0.013) of all acute studies (n = 13), and in 81.8% (74.1-89.4%, p = 0.065) of studies in healthy subgroups (n = 11). Importantly, this effect was apparent in all studies with 'low risk of bias' (n = 8, p = 0.008). In contrast, there was no effect of acute CF interventions at rest. For chronic studies (n = 7), the effect of CFs was less clear, with a significant benefit reported at rest only, in all young, healthy subgroups (n = 7, p = 0.016), but no evidence of improvements in vasodilator responses. CONCLUSIONS CFs have the potential to improve microvascular function, particularly in healthy individuals, with benefits appearing more pronounced following acute CF supplementation. Despite this, interpretations are limited by the small number of comparable studies identified and the heterogeneity of populations studied. Overall, the effects of CFs on the microvasculature seem to be less consistent than previous evidence in the macrovasculature, suggesting that the microvessels may be less susceptible to the effect of CFs than conduit arteries. REGISTRATION The PROSPERO registration number for this review is CRD42023483814.
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Affiliation(s)
- Sophie Richardson
- School of Biomedical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Janice Marshall
- School of Biomedical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
| | - Catarina Rendeiro
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
- Centre for Human Brain Health, University of Birmingham, Birmingham, UK.
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Honda M, Tsuboi A, Minato-Inokawa S, Kitaoka K, Takeuchi M, Yano M, Kurata M, Wu B, Kazumi T, Fukuo K. Association of family history of type 2 diabetes with blood pressure and resting heart rate in young normal weight Japanese women. Diabetol Int 2021; 13:220-225. [DOI: 10.1007/s13340-021-00525-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 07/20/2021] [Indexed: 12/14/2022]
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Abstract
This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies.
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Affiliation(s)
- William B Horton
- Division of Endocrinology and Metabolism, Department of Medicine
| | - Eugene J Barrett
- Division of Endocrinology and Metabolism, Department of Medicine
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia
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Adeva-Andany MM, Funcasta-Calderón R, Fernández-Fernández C, Ameneiros-Rodríguez E, Domínguez-Montero A. Subclinical vascular disease in patients with diabetes is associated with insulin resistance. Diabetes Metab Syndr 2019; 13:2198-2206. [PMID: 31235157 DOI: 10.1016/j.dsx.2019.05.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 05/22/2019] [Indexed: 12/30/2022]
Abstract
Patients with diabetes experience increased cardiovascular risk that is not fully explained by deficient glycemic control or traditional cardiovascular risk factors such as smoking and hypercholesterolemia. Asymptomatic patients with diabetes show structural and functional vascular damage that includes impaired vasodilation, arterial stiffness, increased intima-media thickness and calcification of the arterial wall. Subclinical vascular injury associated with diabetes predicts subsequent manifestations of cardiovascular disease, such as ischemic heart disease, peripheral artery disease and stroke. Noninvasive detection of subclinical vascular disease is commonly used to estimate cardiovascular risk associated to diabetes. Longitudinal studies in normotensive subjects show that arterial stiffness at baseline is associated with a greater risk for future hypertension independently of established risk factors. In patients with type 2 diabetes, vascular disease begins to develop during the latent phase of insulin resistance, long before the clinical diagnosis of diabetes. In contrast, patients with type 1 diabetes do not manifest vascular injury when they are first diagnosed due to insulin deficiency, as they lack the preceding period of insulin resistance. These findings suggest that insulin resistance plays an important role in the development of early vascular disease associated with diabetes. Cross-sectional and prospective studies confirm that insulin resistance is associated with subclinical vascular injury in patients with diabetes, independently of standard cardiovascular risk factors. Asymptomatic vascular disease associated with diabetes begins to occur early in life having been documented in children and adolescents. Insulin resistance should be considered a therapeutic target in order to prevent the vascular complications associated with diabetes.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Hospital General Juan Cardona, C/ Pardo Bazán S/n, 15406, Ferrol, Spain.
| | - Raquel Funcasta-Calderón
- Internal Medicine Department, Hospital General Juan Cardona, C/ Pardo Bazán S/n, 15406, Ferrol, Spain
| | | | - Eva Ameneiros-Rodríguez
- Internal Medicine Department, Hospital General Juan Cardona, C/ Pardo Bazán S/n, 15406, Ferrol, Spain
| | - Alberto Domínguez-Montero
- Internal Medicine Department, Hospital General Juan Cardona, C/ Pardo Bazán S/n, 15406, Ferrol, Spain
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6
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Gateva AT, Assyov YS, Tsakova AD, Kamenov ZA. Serum AGEs and sRAGE levels are not related to vascular complications in patients with prediabetes. Diabetes Metab Syndr 2019; 13:1005-1010. [PMID: 31336435 DOI: 10.1016/j.dsx.2019.01.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 01/17/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND While hyperglycemia has a key role in the pathogenesis of microvascular complications of diabetes, it is just one of the many factors contributing to macrovascular damage. The aim of the present study is to investigate the link between serum pentosidine and sRAGE levels and vascular complications in patients with prediabetes compared to normal glucose tolerance controls with obesity. METHODS In this study were included 76 patients with mean age 50.7 ± 10.7 years, divided into two age and BMI-matched groups - group 1 with obesity without glycemic disturbances (n = 38) and group 2 with obesity and prediabetes (n = 38). RESULTS There was no significant difference in pentosidine and sRAGE levels between patients with obesity and prediabetes. Patients with hypertension had lower levels of sRAGE compared to nonhypertensive subjects. sRAGE showed a weak negative correlation to blood glucose on 60th min of OGTT and HOMA index. There was no correlation between sRAGE and pentosidine levels and the markers of micro- and macrovascular complications. There was no difference in sRAGE and pentosidine levels between patients with and without endothelial dysfunction. CONCLUSIONS sRAGE and pentosidine levels are similar in patients with obesity with and without prediabetes and do not correlate to the markers of micro- and macrovascular complications.
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Affiliation(s)
- Antoaneta T Gateva
- Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University-Sofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria.
| | - Yavor S Assyov
- Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University-Sofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria
| | - Adelina D Tsakova
- Central Clinical Laboratory, University Hospital "Alexandrovska", Medical University-Sofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria
| | - Zdravko A Kamenov
- Clinic of Endocrinology, University Hospital "Alexandrovska", Medical University-Sofia, 1 Georgi Sofiiski str, 1431, Sofia, Bulgaria
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Adeva-Andany MM, Ameneiros-Rodríguez E, Fernández-Fernández C, Domínguez-Montero A, Funcasta-Calderón R. Insulin resistance is associated with subclinical vascular disease in humans. World J Diabetes 2019; 10:63-77. [PMID: 30788044 PMCID: PMC6379732 DOI: 10.4239/wjd.v10.i2.63] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 02/05/2023] Open
Abstract
Insulin resistance is associated with subclinical vascular disease that is not justified by conventional cardiovascular risk factors, such as smoking or hypercholesterolemia. Vascular injury associated to insulin resistance involves functional and structural damage to the arterial wall that includes impaired vasodilation in response to chemical mediators, reduced distensibility of the arterial wall (arterial stiffness), vascular calcification, and increased thickness of the arterial wall. Vascular dysfunction associated to insulin resistance is present in asymptomatic subjects and predisposes to cardiovascular diseases, such as heart failure, ischemic heart disease, stroke, and peripheral vascular disease. Structural and functional vascular disease associated to insulin resistance is highly predictive of cardiovascular morbidity and mortality. Its pathogenic mechanisms remain undefined. Prospective studies have demonstrated that animal protein consumption increases the risk of developing cardiovascular disease and predisposes to type 2 diabetes (T2D) whereas vegetable protein intake has the opposite effect. Vascular disease linked to insulin resistance begins to occur early in life. Children and adolescents with insulin resistance show an injured arterial system compared with youth free of insulin resistance, suggesting that insulin resistance plays a crucial role in the development of initial vascular damage. Prevention of the vascular dysfunction related to insulin resistance should begin early in life. Before the clinical onset of T2D, asymptomatic subjects endure a long period of time characterized by insulin resistance. Latent vascular dysfunction begins to develop during this phase, so that patients with T2D are at increased cardiovascular risk long before the diagnosis of the disease.
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Affiliation(s)
- María M Adeva-Andany
- Internal Medicine Department, Hospital General Juan Cardona, Ferrol 15406, Spain
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de Wert LA, Geerts M, van der Brug S, Adriaansen L, Poeze M, Schaper N, Bouvy ND. The Effect of Shear Force on Skin Viability in Patients with Type 2 Diabetes. J Diabetes Res 2019; 2019:1973704. [PMID: 31781661 PMCID: PMC6875394 DOI: 10.1155/2019/1973704] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 08/02/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Shear is a major risk factor in the development of diabetic foot ulcers, but its effect on the skin of patients with type 2 diabetes mellitus (DM) remains to be elucidated. The aim was to determine skin responses to shear in DM patients with and without diabetic polyneuropathy (DNP). METHODS The forearm skin was loaded with 14.5 N shear (+2.4 kPa pressure) and with 3.5 kPa pressure for 30 minutes in 10 type 2 DM patients without DNP, 10 type 2 DM patients with DNP, and 10 healthy participants. A Sebutape collected IL-1α (measure of tissue damage). A laser Doppler flowmeter measured cutaneous blood cell flux (CBF) as a measure of the reactive hyperaemic skin response. FINDINGS Reactive hyperaemia and IL-1α release was significantly increased after shear loading in all three groups and was higher compared to the responses to pressure loading. The reactive hyperaemic response after shear loading was impaired in patients with type 2 DM compared to healthy participants but did not differ between patients with and without DNP. The reactive hyperaemic response was negatively correlated with the blood glucose level but did not correlate with the DNP severity score. INTERPRETATION Shear is important in the development of tissue damage, but the reparative responses to shear are impaired in patients with type 2 DM. DNP was not associated with altered skin responses, suggesting that the loss of protective sensation to sense shear to skin remains a key factor in the development of diabetic foot ulcers in patients with DNP.
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Affiliation(s)
- Luuk A. de Wert
- Department of General Surgery, Maastricht University Medical Centre, Maastricht, Netherlands
- NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Margot Geerts
- Department of Neurology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Sander van der Brug
- NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Laura Adriaansen
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Martijn Poeze
- Department of General Surgery, Maastricht University Medical Centre, Maastricht, Netherlands
- NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
| | - Nicolaas Schaper
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
- CAPHRI School for Public Health and Primary Care, Maastricht University, Maastricht, Netherlands
| | - Nicole D. Bouvy
- Department of General Surgery, Maastricht University Medical Centre, Maastricht, Netherlands
- NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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9
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Novielli-Kuntz NM, Lemaster KA, Frisbee JC, Jackson DN. Neuropeptide Y1 and alpha-1 adrenergic receptor-mediated decreases in functional vasodilation in gluteus maximus microvascular networks of prediabetic mice. Physiol Rep 2018; 6:e13755. [PMID: 29981203 PMCID: PMC6035337 DOI: 10.14814/phy2.13755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/06/2018] [Accepted: 06/08/2018] [Indexed: 12/27/2022] Open
Abstract
Prediabetes is associated with impaired contraction‐evoked dilation of skeletal muscle arterioles, which may be due to increased sympathetic activity accompanying this early stage of diabetes disease. Herein, we sought to determine whether blunted contraction‐evoked vasodilation resulted from enhanced sympathetic neuropeptide Y1 receptor (Y1R) and alpha‐1 adrenergic receptor (α1R) activation. Using intravital video microscopy, second‐, third‐, and fourth‐order (2A, 3A, and 4A) arteriolar diameters were measured before and following electrical field stimulation of the gluteus maximus muscle (GM) in prediabetic (PD, Pound Mouse) and control (CTRL, c57bl6, CTRL) mice. Baseline diameter was similar between groups; however, single tetanic contraction (100 Hz; 400 and 800 msec) and sustained rhythmic contraction (2 and 8 Hz, 30 sec) evoked rapid onset vasodilation and steady‐state vasodilatory responses that were blunted by 50% or greater in PD versus CTRL. Following Y1R and α1R blockade with sympathetic antagonists BIBP3226 and prazosin, contraction‐evoked arteriolar dilation in PD was restored to levels observed in CTRL. Furthermore, arteriolar vasoconstrictor responses to NPY (10−13–10−8 mol/L) and PE (10−9–10−5 mol/L) were greater in PD versus CTRL at higher concentrations, especially at 3A and 4A. These findings suggest that contraction‐evoked vasodilation in PD is blunted by Y1R and α1R receptor activation throughout skeletal muscle arteriolar networks.
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Affiliation(s)
| | - Kent A Lemaster
- Department of Medical Biophysics, Western University, London, Ontario, Canada
| | - Jefferson C Frisbee
- Department of Medical Biophysics, Western University, London, Ontario, Canada.,Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
| | - Dwayne N Jackson
- Department of Medical Biophysics, Western University, London, Ontario, Canada
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10
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Abstract
Cardiovascular disease (CVD) is the leading cause of mortality in people with type 2 diabetes mellitus (T2DM), yet a significant proportion of the disease burden cannot be accounted for by conventional cardiovascular risk factors. Hypertension occurs in majority of people with T2DM, which is substantially more frequent than would be anticipated based on general population samples. The impact of hypertension is considerably higher in people with diabetes than it is in the general population, suggesting either an increased sensitivity to its effect or a confounding underlying aetiopathogenic mechanism of hypertension associated with CVD within diabetes. In this contribution, we aim to review the changes observed in the vascular tree in people with T2DM compared to the general population, the effects of established anti-diabetes drugs on microvascular outcomes, and explore the hypotheses to account for common causalities of the increased prevalence of CVD and hypertension in people with T2DM.
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Affiliation(s)
- W David Strain
- Diabetes and Vascular Medicine Research Centre, NIHR Exeter Clinical Research Facility and Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter NHS Foundation Trust, Barrack Road, Exeter, EX2 5AX, UK.
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11
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Govoni V, Sanders TAB, Reidlinger DP, Darzi J, Berry SEE, Goff LM, Seed PT, Chowienczyk PJ, Hall WL. Compliance with dietary guidelines affects capillary recruitment in healthy middle-aged men and women. Eur J Nutr 2017; 56:1037-1044. [PMID: 26746219 PMCID: PMC5346414 DOI: 10.1007/s00394-015-1151-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 12/23/2015] [Indexed: 10/27/2022]
Abstract
PURPOSE Healthy microcirculation is important to maintain the health of tissues and organs, most notably the heart, kidney and retina. Single components of the diet such as salt, lipids and polyphenols may influence microcirculation, but the effects of dietary patterns that are consistent with current dietary guidelines are uncertain. It was hypothesized that compliance to UK dietary guidelines would have a favourable effect on skin capillary density/recruitment compared with a traditional British diet (control diet). METHODS A 12-week randomized controlled trial in men and women aged 40-70 years was used to test whether skin microcirculation, measured by skin video-capillaroscopy on the dorsum of the finger, influenced functional capillary density (number of capillaries perfused under basal conditions), structural capillary density (number of anatomical capillaries perfused during finger cuff inflation) and capillary recruitment (percentage difference between structural and functional capillary density). RESULTS Microvascular measures were available for 137 subjects out of the 165 participants randomized to treatment. There was evidence of compliance to the dietary intervention, and participants randomized to follow dietary guidelines showed significant falls in resting supine systolic, diastolic and mean arterial pressure of 3.5, 2.6 and 2.9 mmHg compared to the control diet. There was no evidence of differences in capillary density, but capillary recruitment was 3.5 % (95 % CI 0.2, 6.9) greater (P = 0.04) on dietary guidelines compared with control. CONCLUSIONS Adherence to dietary guidelines may help maintain a healthy microcirculation in middle-aged men and women. This study is registered at www.isrctn.com as ISRCTN92382106.
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Affiliation(s)
- Virginia Govoni
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Thomas A B Sanders
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Dianne P Reidlinger
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Julia Darzi
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Sarah E E Berry
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Louise M Goff
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK
| | - Paul T Seed
- Women's Health Division, King's College London, St Thomas' Hospital, London, UK
| | - Philip J Chowienczyk
- British Heart Foundation Centre, School of Medicine, King's College London, St Thomas' Hospital, London, UK
| | - Wendy L Hall
- Diabetes and Nutritional Sciences Division, Faculty of Life Sciences and Medicine, King's College London, 4.108 Franklin-Wilkins Building, 150 Stamford Street, London, SE1 9NH, UK.
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12
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Stoyneva Z, Velcheva I, Antonova N, Titianova E. Microvascular reactivity to thermal stimulation in patients with diabetes mellitus and polyneuropathy. Clin Hemorheol Microcirc 2017; 65:67-75. [DOI: 10.3233/ch-15107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Z. Stoyneva
- Department of Neurology, University Hospital St. Ivan Rilsky – Sofia, Medical Universities of Sofia and Plovdiv, Bulgaria
| | - I. Velcheva
- Department of Neurology, University Hospital of Neurology and Psychiatry, Medical University, Sofia, Bulgaria
| | - N. Antonova
- Department of Biomechanics, Institute of Mechanics, Bulgarian Academy of Sciences, Sofia, Bulgaria
| | - E. Titianova
- Clinic of Functional Diagnostics of the Nervous System, Military Medical Academy, Sofia, Bulgaria
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13
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Jumar A, Harazny JM, Ott C, Friedrich S, Kistner I, Striepe K, Schmieder RE. Retinal Capillary Rarefaction in Patients with Type 2 Diabetes Mellitus. PLoS One 2016; 11:e0162608. [PMID: 27935938 PMCID: PMC5147800 DOI: 10.1371/journal.pone.0162608] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 08/25/2016] [Indexed: 11/17/2022] Open
Abstract
Purpose In diabetes mellitus type 2, capillary rarefaction plays a pivotal role in the pathogenesis of end-organ damage. We investigated retinal capillary density in patients with early disease. Methods This cross-sectional study compares retinal capillary rarefaction determined by intercapillary distance (ICD) and capillary area (CapA), measured non-invasively and in vivo by scanning laser Doppler flowmetry, in 73 patients with type 2 diabetes, 55 healthy controls and 134 individuals with hypertension stage 1 or 2. Results In diabetic patients, ICD was greater (23.2±5.5 vs 20.2±4.2, p = 0.013) and CapA smaller (1592±595 vs 1821±652, p = 0.019) than in healthy controls after adjustment for differences in cardiovascular risk factors between the groups. Compared to hypertensive patients, diabetic individuals showed no difference in ICD (23.1±5.8, p = 0.781) and CapA (1556±649, p = 0.768). Conclusion In the early stage of diabetes type 2, patients showed capillary rarefaction compared to healthy individuals.
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Affiliation(s)
- Agnes Jumar
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
| | - Joanna M Harazny
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany.,Department of Pathophysiology, University of Warmia and Mazury Olsztyn, Poland
| | - Christian Ott
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
| | - Stefanie Friedrich
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
| | - Iris Kistner
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
| | - Kristina Striepe
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
| | - Roland E Schmieder
- Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Germany
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14
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Combining laser-Doppler flowmetry measurements with spectral analysis to study different microcirculatory effects in human prediabetic and diabetic subjects. Lasers Med Sci 2016; 32:327-334. [DOI: 10.1007/s10103-016-2117-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 11/22/2016] [Indexed: 11/28/2022]
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15
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Lanting SM, Johnson NA, Baker MK, Caterson ID, Chuter VH. The effect of exercise training on cutaneous microvascular reactivity: A systematic review and meta-analysis. J Sci Med Sport 2016; 20:170-177. [PMID: 27476375 DOI: 10.1016/j.jsams.2016.04.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 03/29/2016] [Accepted: 04/12/2016] [Indexed: 10/21/2022]
Abstract
OBJECTIVES This study aimed to review the efficacy of exercise training for improving cutaneous microvascular reactivity in response to local stimulus in human adults. DESIGN Systematic review with meta-analysis. METHODS A systematic search of Medline, Cinahl, AMED, Web of Science, Scopus, and Embase was conducted up to June 2015. Included studies were controlled trials assessing the effect of an exercise training intervention on cutaneous microvascular reactivity as instigated by local stimulus such as local heating, iontophoresis and post-occlusive reactive hyperaemia. Studies where the control was only measured at baseline or which included participants with vasospastic disorders were excluded. Two authors independently reviewed and selected relevant controlled trials and extracted data. Quality was assessed using the Downs and Black checklist. RESULTS Seven trials were included, with six showing a benefit of exercise training but only two reaching statistical significance with effect size ranging from -0.14 to 1.03. The meta-analysis revealed that aerobic exercise had a moderate statistically significant effect on improving cutaneous microvascular reactivity (effect size (ES)=0.43, 95% CI: 0.08-0.78, p=0.015). CONCLUSIONS Individual studies employing an exercise training intervention have tended to have small sample sizes and hence lacked sufficient power to detect clinically meaningful benefits to cutaneous microvascular reactivity. Pooled analysis revealed a clear benefit of exercise training on improving cutaneous microvascular reactivity in older and previously inactive adult cohorts. Exercise training may provide a cost-effective option for improving cutaneous microvascular reactivity in adults and may be of benefit to those with cardiovascular disease and metabolic disorders such as diabetes.
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Affiliation(s)
- Sean M Lanting
- School of Health Sciences, University of Newcastle, Australia.
| | - Nathan A Johnson
- Faculty of Health Sciences, University of Sydney, Australia; Charles Perkins Centre, University of Sydney, Australia
| | - Michael K Baker
- School of Exercise Science, Australian Catholic University, Australia
| | | | - Vivienne H Chuter
- School of Health Sciences, University of Newcastle, Australia; Priority Research Centre for Physical activity and Nutrition, University of Newcastle, Australia
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Østergaard L, Finnerup NB, Terkelsen AJ, Olesen RA, Drasbek KR, Knudsen L, Jespersen SN, Frystyk J, Charles M, Thomsen RW, Christiansen JS, Beck-Nielsen H, Jensen TS, Andersen H. The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy. Diabetologia 2015; 58:666-77. [PMID: 25512003 PMCID: PMC4351434 DOI: 10.1007/s00125-014-3461-z] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 11/06/2014] [Indexed: 12/14/2022]
Abstract
Diabetic neuropathy is associated with disturbances in endoneurial metabolism and microvascular morphology, but the roles of these factors in the aetiopathogenesis of diabetic neuropathy remain unclear. Changes in endoneurial capillary morphology and vascular reactivity apparently predate the development of diabetic neuropathy in humans, and in manifest neuropathy, reductions in nerve conduction velocity correlate with the level of endoneurial hypoxia. The idea that microvascular changes cause diabetic neuropathy is contradicted, however, by reports of elevated endoneurial blood flow in early experimental diabetes, and of unaffected blood flow when early histological signs of neuropathy first develop in humans. We recently showed that disturbances in capillary flow patterns, so-called capillary dysfunction, can reduce the amount of oxygen and glucose that can be extracted by the tissue for a given blood flow. In fact, tissue blood flow must be adjusted to ensure sufficient oxygen extraction as capillary dysfunction becomes more severe, thereby changing the normal relationship between tissue oxygenation and blood flow. This review examines the evidence of capillary dysfunction in diabetic neuropathy, and whether the observed relation between endoneurial blood flow and nerve function is consistent with increasingly disturbed capillary flow patterns. The analysis suggests testable relations between capillary dysfunction, tissue hypoxia, aldose reductase activity, oxidative stress, tissue inflammation and glucose clearance from blood. We discuss the implications of these predictions in relation to the prevention and management of diabetic complications in type 1 and type 2 diabetes, and suggest ways of testing these hypotheses in experimental and clinical settings.
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Affiliation(s)
- Leif Østergaard
- Center of Functionally Integrative Neuroscience and MINDLab, Institute of Clinical Medicine, Aarhus University Hospital, Building 10G, Nørrebrogade 44, DK-8000, Aarhus C, Denmark,
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Bond B, Gates PE, Jackman SR, Corless LM, Williams CA, Barker AR. Exercise intensity and the protection from postprandial vascular dysfunction in adolescents. Am J Physiol Heart Circ Physiol 2015; 308:H1443-50. [PMID: 25820392 DOI: 10.1152/ajpheart.00074.2015] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/24/2015] [Indexed: 12/26/2022]
Abstract
Acute exercise transiently improves endothelial function and protects the vasculature from the deleterious effects of a high-fat meal (HFM). We sought to identify whether this response is dependent on exercise intensity in adolescents. Twenty adolescents (10 male, 14.3 ± 0.3 yr) completed three 1-day trials: 1) rest (CON); 2) 8 × 1 min cycling at 90% peak power with 75 s recovery [high-intensity interval exercise (HIIE)]; and 3) cycling at 90% of the gas exchange threshold [moderate-intensity exercise (MIE)] 1 h before consuming a HFM (1.50 g/kg fat). Macrovascular and microvascular endothelial function was assessed before and immediately after exercise and 3 h after the HFM by flow-mediated dilation (FMD) and laser Doppler imaging [peak reactive hyperemia (PRH)]. FMD and PRH increased 1 h after HIIE [P < 0.001, effect size (ES) = 1.20 and P = 0.048, ES = 0.56] but were unchanged after MIE. FMD and PRH were attenuated 3 h after the HFM in CON (P < 0.001, ES = 1.78 and P = 0.02, ES = 0.59). FMD remained greater 3 h after the HFM in HIIE compared with MIE (P < 0.001, ES = 1.47) and CON (P < 0.001, ES = 2.54), and in MIE compared with CON (P < 0.001, ES = 1.40). Compared with CON, PRH was greater 3 h after the HFM in HIIE (P = 0.02, ES = 0.71) and MIE (P = 0.02, ES = 0.84), with no differences between HIIE and MIE (P = 0.72, ES = 0.16). Plasma triacylglycerol concentration and total antioxidant status concentration were not different between trials. We conclude that exercise intensity plays an important role in protecting the vasculature from the deleterious effects of a HFM. Performing HIIE may provide superior vascular benefits than MIE in adolescent groups.
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Affiliation(s)
- B Bond
- Children's Health and Exercise Research Centre, Sport and Health Science, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom
| | - P E Gates
- Diabetes and Vascular Medicine, University of Exeter Medical School, Exeter, United Kingdom; and
| | - S R Jackman
- Sport and Health Science, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom
| | - L M Corless
- Sport and Health Science, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom
| | - C A Williams
- Children's Health and Exercise Research Centre, Sport and Health Science, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom
| | - A R Barker
- Children's Health and Exercise Research Centre, Sport and Health Science, College of Life and Environmental Sciences, University of Exeter, Exeter, United Kingdom;
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Aygün F, Efe D. Association of neutrophil/lymphocyte ratio with obstructive coronary artery disease and coronary artery calcium score detected by multislice computed tomography in type 2 diabetes mellitus patients. Patient Prefer Adherence 2015; 9:1023-31. [PMID: 26229449 PMCID: PMC4514314 DOI: 10.2147/ppa.s85577] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the association of neutrophil/lymphocyte ratio (NLR) with coronary artery calcium score (CACS) and obstructive coronary artery disease (CAD) detected by multislice computed tomography (MSCT) angiography in type 2 diabetes mellitus (T2DM) patients. METHODS Two hundred and ninety-two T2DM patients, who were either asymptomatic or symptomatic (but noncharacteristic) for coronary artery disease (CAD) and underwent MSCT angiography in our clinic between May 2009 and June 2014, were enrolled. All patients were divided into two groups according to their mean NLR values. Patients with NLR ≤2.05 were assigned to Group 1 and patients with NLR >2.05 were assigned to Group 2. The association of NLR with CACS and obstructive CAD, which were detected by MSCT angiography, was investigated in T2DM patients. RESULTS According to the Agatston scoring method, the mean CACS was 129.5±209.8 Au in Group 1 and 290.3±399.6 Au in Group 2 (P<0.001). Obstructive CAD was detected in 40 (26.8%) patients in Group 1 and in 56 (39.2%) patients in Group 2 (P<0.05, P<0.021). CONCLUSION The rate of obstructive CAD was significantly higher in the T2DM patients with NLR >2.05 than that in the T2DM patients with NLR ≤2.05. In addition, the CACS was also significantly higher in the T2DM patients with NLR >2.05 than that in the T2DM patients with NLR ≤2.05.
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Affiliation(s)
- Fatih Aygün
- Department of Cardiovascular Surgery, Konya Medical and Research Center, Başkent University, Konya, Turkey
- Correspondence: Fatih Aygün, Hocacihan Mahalle Saray Cad No 1, 42000 Selçuklu, Konya, Turkey, Tel +90 332 322 94 10, Fax +90 332 322 94 19, Email
| | - Duran Efe
- Department of Radiology, Faculty of Medicine, Mevlana University, Konya, Turkey
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Wavelet-analysis of skin temperature oscillations during local heating for revealing endothelial dysfunction. Microvasc Res 2015; 97:109-14. [DOI: 10.1016/j.mvr.2014.10.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 10/16/2014] [Accepted: 10/17/2014] [Indexed: 11/23/2022]
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Kubota T, Kubota N, Kadowaki T. The role of endothelial insulin signaling in the regulation of glucose metabolism. Rev Endocr Metab Disord 2013; 14:207-16. [PMID: 23589150 DOI: 10.1007/s11154-013-9242-z] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The skeletal muscle is one of the major target organs of insulin and plays an essential role in insulin-induced glucose uptake. Some evidence indicates that insulin delivery to skeletal muscle interstitium through the endothelial cells is the rate-limiting step in insulin-stimulated glucose uptake. Researchers have also found that this process is impaired by insulin resistance in type 2 diabetes and obesity. A recent study of ours demonstrated that insulin signaling in the endothelial cells plays a pivotal role in the regulation of glucose uptake by the skeletal muscle. Specifically, impaired insulin signaling in the endothelial cells, with reduction of insulin-induced eNOS phosphorylation, causes attenuation of the insulin-induced capillary recruitment and insulin delivery, which, in turn reduces glucose uptake by the skeletal muscle in high-fat diet-fed mice. Moreover, restoration of the insulin-induced eNOS phosphorylation in the endothelial cells completely reverses the reduction in the capillary recruitment and insulin delivery, and as a result, significantly restores glucose uptake by the skeletal muscle. In the present review, we describe the recent progress in research on the physiological and pathophysiological roles of endothelial insulin signaling in the regulation of insulin-induced glucose uptake by the skeletal muscle.
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Affiliation(s)
- Tetsuya Kubota
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
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Sprague RS, Ellsworth ML. Erythrocyte-derived ATP and perfusion distribution: role of intracellular and intercellular communication. Microcirculation 2012; 19:430-9. [PMID: 22775760 PMCID: PMC3324633 DOI: 10.1111/j.1549-8719.2011.00158.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
In complex organisms, both intracellular and intercellular communication are critical for the appropriate regulation of the distribution of perfusion to assure optimal O(2) delivery and organ function. The mobile erythrocyte is in a unique position in the circulation as it both senses and responds to a reduction in O(2) tension in its environment. When erythrocytes enter a region of the microcirculation in which O(2) tension is reduced, they release both O(2) and the vasodilator, ATP, via activation of a specific and dedicated signaling pathway that requires increases in cAMP, which are regulated by PDE3B. The ATP released initiates a conducted vasodilation that results in alterations in the distribution of perfusion to meet the tissue's metabolic needs. This delivery mechanism is modulated by both positive and negative feedback regulators. Importantly, defects in low O(2) -induced ATP release from erythrocytes have been observed in several human disease states in which impaired vascular function is present. Understanding of the role of erythrocytes in controlling perfusion distribution and the signaling pathways that are responsible for ATP release from these cells makes the erythrocyte a novel therapeutic target for the development of new approaches for the treatment of vascular dysfunction.
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Affiliation(s)
- Randy S Sprague
- Saint Louis University School of Medicine, St. Louis, Missouri, USA.
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Strain WD, Adingupu DD, Shore AC. Microcirculation on a large scale: techniques, tactics and relevance of studying the microcirculation in larger population samples. Microcirculation 2012; 19:37-46. [PMID: 21972935 DOI: 10.1111/j.1549-8719.2011.00140.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The role of microcirculatory dysfunction is increasingly being recognized in the etiopathogenesis of cardiovascular disease. Whilst the importance of detailed mechanistic studies to determine the exact nature of these disturbances is without question, it was large-scale population-based studies that first identified the associations between deranged microvascular perfusion, autoregulation or structure, and subsequent target organ damage. This is the subject of considerable studies to establish whether there is a causal effect in either direction, or simply represents shared risk factors, although it is most likely to be a complex combination of bidirectional interactions. The techniques for investigating microcirculatory function have evolved almost exponentially over the last 75 years: So too have the strategies for investigation. Current epidemiological studies are focusing on attempting to untangle the inter-relationship between risk factors and pathological mechanisms to attempt to determine whether these represent therapeutic targets or simple markers of unmeasured risk. We plan to review the techniques used for these population-based studies, the advances made, and the clinical implications derived.
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Affiliation(s)
- W David Strain
- Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Diabetes and Vascular Research Centre, Royal Devon & Exeter NHS Foundation Trust, Exeter, UK.
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Jansson PA, Murdolo G, Sjögren L, Nyström B, Sjöstrand M, Strindberg L, Lönnroth P. Tadalafil increases muscle capillary recruitment and forearm glucose uptake in women with type 2 diabetes. Diabetologia 2010; 53:2205-8. [PMID: 20535445 PMCID: PMC2931646 DOI: 10.1007/s00125-010-1819-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2010] [Accepted: 05/18/2010] [Indexed: 11/17/2022]
Abstract
AIMS/HYPOTHESIS Recent evidence suggests that reduced synthesis of nitric oxide in endothelial cells, i.e. endothelial dysfunction, contributes to the impaired action of insulin in the vasculature of patients with type 2 diabetes. We investigated whether selective inhibition of phosphodiesterase-5 by tadalafil has beneficial effects on peripheral microcirculation and glucose uptake in these patients. METHODS We enrolled seven postmenopausal women with type 2 diabetes and ten age-matched healthy women as controls in a placebo-controlled study to evaluate the acute metabolic effects of tadalafil. We performed microdialysis and blood flow measurements in muscle, and sampled arterial and deep venous blood before and after a single dose of tadalafil 20 mg or placebo. Circulating glucose and insulin levels, muscle capillary recruitment as reflected by permeability surface area for glucose (PS(glu)) and forearm glucose uptake were measured. RESULTS In women with type 2 diabetes, but not in the control group, tadalafil induced increases in the incremental AUC for PS(glu) (tadalafil vs placebo 41 +/- 11 vs 4 +/- 2 ml [100 g](-1) min(-1), p < 0.05) and forearm glucose uptake (46 +/- 9 vs 8 +/- 4 micromol [100 g](-1) min(-1), p < 0.05). The variable that best predicted forearm glucose uptake was PS(glu), which explained 70% of its variance. However, fasting glucose and insulin concentrations were similar following treatment with placebo or tadalafil in the two groups. CONCLUSIONS/INTERPRETATION This study suggests that tadalafil evokes positive metabolic effects in insulin-resistant women with type 2 diabetes.
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Affiliation(s)
- P-A Jansson
- The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg, Blå Stråket 5, S-413 45 Göteborg, Sweden.
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Li R, Lau WB, Ma XL. Adiponectin resistance and vascular dysfunction in the hyperlipidemic state. Acta Pharmacol Sin 2010; 31:1258-66. [PMID: 20802503 PMCID: PMC4012912 DOI: 10.1038/aps.2010.95] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2010] [Accepted: 06/22/2010] [Indexed: 12/16/2022]
Abstract
Insulin plays an important role in the stimulation of vascular nitric oxide production, with both short term (vasomotility and anti-thrombotic effects) and long term (smooth muscle cell growth and migration inhibition) benefits. Impaired vasodilatory response to insulin, the hallmark of vascular insulin resistance (IR), has important implications for circulatory pathophysiology. An association between adipokines and IR has been observed in both diabetic and nondiabetic states. Adiponectin (APN) is an insulin-sensitizing adipokine known to stimulate skeletal muscle fatty acid (FA) oxidation and reduce lipid accumulation. Recent demonstrations of potential cross-talk between APN and insulin in vascular function regulation are particularly interesting. The lipid accumulation observed after chronic high-fat (HF) diets and in the obese state may reduce vascular response to APN, a pathologic state termed as APN resistance. This review highlights the importance of insulin sensitivity and APN activity in the maintenance of endothelial function. It explores the relationships between vascular IR and APN resistance in the hyperlipidemic pathological condition, representative of the metabolic syndrome. The investigation of vascular insulin and APN resistance provides not only better understanding of vascular pathophysiology, but also an opportunity for therapeutic targeting in individuals affected by the metabolic syndrome.
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Affiliation(s)
- Rong Li
- Department of Geriatrics, Xijing Hospital, Xi-an 710032, China
| | - Wayne Bond Lau
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Xin Liang Ma
- Department of Geriatrics, Xijing Hospital, Xi-an 710032, China
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Sprague RS, Goldman D, Bowles EA, Achilleus D, Stephenson AH, Ellis CG, Ellsworth ML. Divergent effects of low-O(2) tension and iloprost on ATP release from erythrocytes of humans with type 2 diabetes: implications for O(2) supply to skeletal muscle. Am J Physiol Heart Circ Physiol 2010; 299:H566-73. [PMID: 20511412 DOI: 10.1152/ajpheart.00430.2010] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Erythrocytes release both O(2) and a vasodilator, ATP, when exposed to reduced O(2) tension. We investigated the hypothesis that ATP release is impaired in erythrocytes of humans with type 2 diabetes (DM2) and that this defect compromises the ability of these cells to stimulate dilation of resistance vessels. We also determined whether a general vasodilator, the prostacyclin analog iloprost (ILO), stimulates ATP release from healthy human (HH) and DM2 erythrocytes. Finally, we used a computational model to compare the effect on tissue O(2) levels of increases in blood flow directed to areas of increased O(2) demand (erythrocyte ATP release) with nondirected increases in flow (ILO). HH erythrocytes, but not DM2 cells, released increased amounts of ATP when exposed to reduced O(2) tension (Po(2) < 30 mmHg). In addition, isolated hamster skeletal muscle arterioles dilated in response to similar decreases in extraluminal O(2) when perfused with HH erythrocytes, but not when perfused with DM2 erythrocytes. In contrast, both HH and DM2 erythrocytes released ATP in response to ILO. In the case of DM2 erythrocytes, amounts of ATP released correlated inversely with glycemic control. Modeling revealed that a functional regulatory system that directs blood flow to areas of need (low O(2)-induced ATP release) provides appropriate levels of tissue oxygenation and that this level of the matching of O(2) delivery with demand in skeletal muscle cannot be achieved with a general vasodilator. These results suggest that the inability of erythrocytes to release ATP in response to exposure to low-O(2) tension could contribute to the peripheral vascular disease of DM2.
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Affiliation(s)
- Randy S Sprague
- Dept. of Pharmacological and Physiological Science, Saint Louis Univ. School of Medicine, 1402 S. Grand Blvd., St. Louis, MO 63104, USA.
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Ellis CG, Goldman D, Hanson M, Stephenson AH, Milkovich S, Benlamri A, Ellsworth ML, Sprague RS. Defects in oxygen supply to skeletal muscle of prediabetic ZDF rats. Am J Physiol Heart Circ Physiol 2010; 298:H1661-70. [PMID: 20207810 DOI: 10.1152/ajpheart.01239.2009] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In humans, prediabetes is characterized by marked increases in plasma insulin and near normal blood glucose levels as well as microvascular dysfunction of unknown origin. Using the extensor digitorum longus muscle of 7-wk inbred male Zucker diabetic fatty rats fed a high-fat diet as a model of prediabetes, we tested the hypothesis that hyperinsulinemia contributes to impaired O(2) delivery in skeletal muscle. Using in vivo video microscopy, we determined that the total O(2) supply to capillaries in the extensor digitorum longus muscle of prediabetic rats was reduced to 64% of controls with a lower O(2) supply rate per capillary and higher O(2) extraction resulting in a decreased O(2) saturation at the venous end of the capillary network. These findings suggest a lower average tissue Po(2) in prediabetic animals. In addition, we determined that insulin, at concentrations measured in humans and Zucker diabetic fatty rats with prediabetes, inhibited the O(2)-dependent release of ATP from rat red blood cells (RBCs). This inability to release ATP could contribute to the impaired O(2) delivery observed in rats with prediabetes, especially in light of the finding that the endothelium-dependent relaxation of resistance arteries from these animals is not different from controls and is not altered by insulin. Computational modeling confirmed a significant 8.3-mmHg decrease in average tissue Po(2) as well as an increase in the heterogeneity of tissue Po(2), implicating a failure of a regulatory system for O(2) supply. The finding that insulin attenuates the O(2)-dependent release of ATP from RBCs suggests that this defect in RBC physiology could contribute to a failure in the regulation of O(2) supply to meet the demand in skeletal muscle in prediabetes.
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Affiliation(s)
- Christopher G Ellis
- Dept. of Medical Biophysics, Univ. of Western Ontario, London, ON, N6A 5C1, Canada.
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Hanson MS, Stephenson AH, Bowles EA, Sprague RS. Insulin inhibits human erythrocyte cAMP accumulation and ATP release: role of phosphodiesterase 3 and phosphoinositide 3-kinase. Exp Biol Med (Maywood) 2010; 235:256-62. [PMID: 20404042 PMCID: PMC2892266 DOI: 10.1258/ebm.2009.009206] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
In non-erythroid cells, insulin stimulates a signal transduction pathway that results in the activation of phosphoinositide 3-kinase (PI3K) and subsequent phosphorylation of phosphodiesterase 3 (PDE3). Erythrocytes possess insulin receptors, PI3K and PDE3B. These cells release adenosine triphosphate (ATP) when exposed to reduced O(2) tension via a signaling pathway that requires activation of the G protein, Gi, as well as increases in cAMP. Although insulin inhibits ATP release from human erythrocytes in response to Gi activation by mastoparan 7 (Mas 7), no effect on cAMP was described. Here, we investigated the hypothesis that insulin activates PDE3 in human erythrocytes via a PI3K-mediated mechanism resulting in cAMP hydrolysis and inhibition of ATP release. Incubation of human erythrocytes with Mas 7 resulted in a 62 +/- 7% increase in cAMP (n = 9, P < 0.05) and a 306 +/- 69% increase in ATP release (n = 9, P < 0.05), both of which were attenuated by pre-treatment with insulin. Selective inhibitors of PDE3 (cilostazol) or PI3K (LY294002) rescued these effects of insulin. These results support the hypothesis that insulin activates PDE3 in erythrocytes via a PI3K-dependent mechanism. Once activated, PDE3 limits Mas 7-induced increases in intracellular cAMP. This effect of insulin leads, ultimately, to decreased ATP release in response to Mas 7. Activation of Gi is required for reduced O(2) tension-induced ATP release from erythrocytes and this ATP release has been shown to participate in the matching of O(2) supply with demand in skeletal muscle. Thus, pathological increases in circulating insulin could, via activation of PDE3 in erythrocytes, inhibit ATP release from these cells, depriving the peripheral circulation of one mechanism that could aid in the regulation of the delivery of O(2) to meet tissue metabolic need.
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Affiliation(s)
- Madelyn S Hanson
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St Louis, MO 63104, USA.
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29
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Green AQ, Krishnan ST, Rayman G. C-fiber function assessed by the laser doppler imager flare technique and acetylcholine iontophoresis. Muscle Nerve 2009; 40:985-91. [DOI: 10.1002/mus.21333] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Östlund Papadogeorgos N, Bengtsson M, Kalani M. Selective endothelin A-receptor blockade attenuates coronary microvascular dysfunction after coronary stenting in patients with type 2 diabetes. Vasc Health Risk Manag 2009; 5:893-9. [PMID: 19898645 PMCID: PMC2773748 DOI: 10.2147/vhrm.s7867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Endothelin-1 may be involved in the development of diabetic microangiopathy. We studied the effect of endothelin-1 blockade on myocardial microcirculation during coronary stenting. PATIENTS AND METHODS Patients with type 2 diabetes and stable coronary artery disease undergoing elective percutaneous coronary intervention (PCI) were randomized to bolus dose of 500 mg bosentan (n = 4), a dual endothelin receptor blocker, or intracoronary administration of 0.03 mmol BQ123 (n = 6), a selective endothelin A-receptor blocker, or placebo (n = 5), respectively. Coronary flow reserve (CFR) was measured immediately post-PCI. CFR was also measured in five nondiabetic controls post-coronary stenting. RESULTS Patients in the placebo group had (P < 0.05) lower values of CFR (2.3 +/- 1.2) as compared to those who received endothelin blockade (n = 10; 3.1 +/- 0.7) and nondiabetic controls (4.9 +/- 2.3). Patients who received BQ123 showed significantly higher CFR (3.3 +/- 0.5; P < 0.05) as compared to those on placebo. Nondiabetic patients had significantly higher CFR as compared to patients with diabetes (4.9 +/- 2.3 and 2.8 +/- 1.0, respectively; P < 0.05). CONCLUSION Coronary microvascular dysfunction is present during coronary stenting in patients with type 2 diabetes and may be reversed by selective endothelin A-receptor blockade. Targeting endothelin system may be of importance in protecting the myocardium against ischemic events during elective PCI in type 2 diabetic patients.
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Affiliation(s)
| | - Mattias Bengtsson
- Karolinska Institute, Department of Clinical Sciences, Department of Cardiology, Danderyd Hospital, Stockholm, Sweden
| | - Majid Kalani
- Karolinska Institute, Department of Clinical Sciences, Department of Cardiology, Danderyd Hospital, Stockholm, Sweden
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Abstract
Diabetic foot disease and ulceration is a major complication that may lead to the amputation of the lower limbs. Microangiopathy may play a significant role in the pathogenesis of tissue breakdown in the diabetic foot. However, the precise mechanisms of this process remain unclear and poorly understood. Microvasculature in the skin is comprised of nutritive capillaries and thermoregulatory arteriovenous shunt flow. It is regulated through the complex interaction of neurogenic and neurovascular control. The interplay among endothelial dysfunction, impaired nerve axon reflex activities, and microvascular regulation in the diabetic patient results in the poor healing of wounds. Skin microvasculature undergoes both morphologic changes as well as functional deficits when parts of the body come under stress or injury. Two important theories that have been put forward to explain the abnormalities that have been observed are the haemodynamic hypothesis and capillary steal syndrome. With advances in medical technology, microvasculature can now be measured quantitatively. This article reviews the development of microvascular dysfunction in the diabetic foot and discusses how it may relate to the pathogenesis of diabetic foot problems and ulceration. Common methods for measuring skin microcirculation are also discussed.
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Affiliation(s)
- Clare Y L Chao
- Physiotherapy Department, Queen Elizabeth Hospital, Hong Kong SAR, China
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Hanson MS, Ellsworth ML, Achilleus D, Stephenson AH, Bowles EA, Sridharan M, Adderley S, Sprague RS. Insulin inhibits low oxygen-induced ATP release from human erythrocytes: implication for vascular control. Microcirculation 2009; 16:424-33. [PMID: 19412833 PMCID: PMC2906128 DOI: 10.1080/10739680902855218] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE ATP released from human erythrocytes in response to reduced oxygen tension (pO(2)) participates in the matching of oxygen (O(2)) supply with need in skeletal muscle by stimulating increases in blood flow to areas with increased O(2) demand. Here, we investigated the hypothesis that hyperinsulinemia inhibits ATP release from erythrocytes and impairs their ability to stimulate dilation of isolated arterioles exposed to decreased extraluminal pO(2). MATERIALS AND METHODS Erythrocyte ATP release was stimulated pharmacologically (mastoparan 7) and physiologically (reduced pO(2)) in the absence or presence of insulin. We also examined the ability of isolated skeletal muscle arterioles perfused with buffer containing erythrocytes treated with insulin or its vehicle (saline) to dilate in response to decreased extraluminal pO(2). RESULTS Insulin significantly attenuated mastoparan 7- and reduced pO(2)-induced ATP release. In vessels perfused with untreated erythrocytes, low extraluminal pO(2) resulted in an increase in vessel diameter. In contrast, when erythrocytes were treated with insulin, no vasodilation occurred. CONCLUSIONS These studies demonstrate that insulin inhibits ATP release from erythrocytes in response to reduced pO(2) and impairs their ability to stimulate dilation of skeletal muscle arterioles. These results suggest that hyperinsulinemia could hinder the matching of O(2) supply with need in skeletal muscle.
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Affiliation(s)
- Madelyn S Hanson
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
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Beer S, Feihl F, Ruiz J, Juhan-Vague I, Aillaud MF, Wetzel SG, Liaudet L, Gaillard RC, Waeber B. Comparison of skin microvascular reactivity with hemostatic markers of endothelial dysfunction and damage in type 2 diabetes. Vasc Health Risk Manag 2009; 4:1449-58. [PMID: 19337558 PMCID: PMC2663449 DOI: 10.2147/vhrm.s4175] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Aim: Patients with non-insulin-dependent diabetes mellitus (NIDDM) are at increased cardiovascular risk due to an accelerated atherosclerotic process. The present study aimed to compare skin microvascular function, pulse wave velocity (PWV), and a variety of hemostatic markers of endothelium injury [von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA), tissue factor pathway inhibitor (TFPI), and the soluble form of thrombomodulin (s-TM)] in patients with NIDDM. Methods: 54 patients with NIDDM and 38 sex- and age-matched controls were studied. 27 diabetics had no overt micro- and/or macrovascular complications, while the remainder had either or both. The forearm skin blood flow was assessed by laser-Doppler imaging, which allowed the measurement of the response to iontophoretically applied acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation), as well as the reactive hyperemia triggered by the transient occlusion of the circulation. Results: Both endothelial and non-endothelial reactivity were significantly blunted in diabetics, regardless of the presence or the absence of vascular complications. Plasma vWF, TFPI and s-TM levels were significantly increased compared with controls only in patients exhibiting vascular complications. Concentrations of t-PA and PAI-1 were significantly increased in the two groups of diabetics versus controls. Conclusion: In NIDDM, both endothelium-dependent and -independent microvascular skin reactivity are impaired, whether or not underlying vascular complications exist. It also appears that microvascular endothelial dysfunction is not necessarily associated in NIDDM with increased circulating levels of hemostatic markers of endothelial damage known to reflect a hypercoagulable state.
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Affiliation(s)
- Sandra Beer
- Division de Physiopathologie Clinique, Centre Hospitalier Universitaire Vaudois et Université de Lausanne, Lausanne, Switzerland
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Abstract
Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ETA receptor antagonists are discussed.
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Affiliation(s)
- Majid Kalani
- Department of Clinical Sciences, Karolinska Institutet, Dept of Cardiology, Danderyd Hospital, Stockholm, Sweden.
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Nguyen TT, Wang JJ, Islam FMA, Mitchell P, Tapp RJ, Zimmet PZ, Simpson R, Shaw J, Wong TY. Retinal arteriolar narrowing predicts incidence of diabetes: the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study. Diabetes 2008; 57:536-9. [PMID: 18086902 DOI: 10.2337/db07-1376] [Citation(s) in RCA: 75] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To examine the relationship of retinal vascular caliber to incident diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS The Australian Diabetes, Obesity and Lifestyle (AusDiab) Study recruited adults aged 25+ years across Australia in 1999-2000, with a follow-up 5 years later in 2004-2005. Participants' glycemic status was classified using fasting plasma glucose (FPG) and 2-h oral glucose tolerance (2-h plasma glucose [2hPG]) tests. Diabetes was diagnosed if FPG was >or=7.0 mmol/l or 2hPG was >or=11.1 mmol/l. Retinal vascular caliber was measured from baseline retinal photographs using a computer-assisted program. RESULTS Of the 803 participants without diabetes at baseline, 108 (13.4%) developed diabetes at follow-up: 7 (2.8%) of 246 participants with normal glucose tolerance, 9 (13.6%) of 66 participants with impaired fasting glucose, and 92 (18.7%) of 491 participants with impaired glucose tolerance. After multivariate analysis, participants with narrower retinal arteriolar caliber had a higher risk of diabetes (odds ratio 2.21 [95% CI 1.02-4.80], comparing smallest versus highest arteriolar caliber tertiles, P = 0.04 for trend). There was no association between retinal venular caliber and incident diabetes. CONCLUSIONS Narrower retinal arteriolar caliber predicted risk of diabetes. These data provide further evidence that microvascular changes may contribute to the pathogenesis of diabetes.
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Affiliation(s)
- Thanh T Nguyen
- Centre for Eye Research Australia, University of Melbourne, 32 Gisborne St., East Melbourne 3002, Australia
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Baker N, Green A, Krishnan S, Rayman G. Microvascular and C-fiber function in diabetic charcot neuroarthropathy and diabetic peripheral neuropathy. Diabetes Care 2007; 30:3077-9. [PMID: 17804679 DOI: 10.2337/dc07-1063] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Sympathetic denervation and hyperemia are implicated in the pathogenesis of Charcot neuroarthropathy (CN) but are also features of diabetic peripheral neuropathy (DPN). Differences in these physiological parameters were sought by determining C-fiber function (laser Doppler imager [LDI]flare technique) and maximum microvascular hyperemia (MMH) in 13 subjects with diabetic CN (DCN), 10 subjects with DPN, and 10 healthy control subjects. Additionally, unaffected limbs of the nine DCN subjects with unilateral CN (UCN) were studied to determine whether any observed differences precede CN. RESULTS LDIflare area was reduced in DPN (mean +/- SD 1.41 +/- 0.51 cm(2)) and DCN (1.42 +/- 0.37) groups compared with the healthy control group (5.24 +/- 1.33; P < 0.0001). MMH was higher in DCN (432 +/- 88 PU [perfusion units]) than in DPN (262 +/- 71; P = 0.001) subjects but lower than in the control group (564 +/- 112; P < 0.01). LDIflare area and MMH were similar in the UCN and DCN groups. CONCLUSIONS C-fiber function is equally impaired in neuropathic patients with and without CN; however, a higher MMH distinguishes those with CN. Unaffected and affected limbs of those with unilateral CN have the same neurovascular abnormalities, suggesting that these abnormalities precede CN and are not a result of CN.
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Affiliation(s)
- Neil Baker
- Ipswich Diabetic Foot Unit and Diabetes Centre, Suffolk, UK
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Schmiedel O, Schroeter ML, Harvey JN. Microalbuminuria in Type 2 diabetes indicates impaired microvascular vasomotion and perfusion. Am J Physiol Heart Circ Physiol 2007; 293:H3424-31. [PMID: 17933972 DOI: 10.1152/ajpheart.00558.2007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aims were to assess the relationship of vasomotion to perfusion in the cutaneous microcirculation of diabetic patients, to determine the influence on it of endothelium-dependent and nonendothelium-dependent vasodilatory stimuli, and to assess the relationship to perfusion and vasomotion of various biochemical markers of vascular function (HbA1c, LDL- and HDL-cholesterol, triglycerides, insulin resistance, high sensitive C-reactive protein, L- and E-selectin, soluble ICAM, von Willebrand factor) and microalbuminuria. Perfusion and vasomotion (spectral density at low and very low frequencies) were measured by laser-Doppler flowmetry after local heat and iontophoresis of ACh and sodium nitroprusside. Perfusion responses to all stimuli were impaired in patients with Type 2 diabetes (heat: F = 28.0, P < 0.001; ACh: F = 7.11, P = 0.003; sodium nitroprusside: F = 4.0, P = 0.028). Responses to endothelium-dependent stimuli were further impaired in microalbuminuric patients (heat: P = 0.035; ACh: P = 0.034). Vasomotion responses at low frequencies after endothelium-dependent stimuli were impaired in diabetic patients compared with that shown in controls (heat: F = 5.62, P = 0.002; ACh: F = 4.32, P = 0.015). Multivariate modeling showed microalbuminuria to be the only consistent predictor of perfusion and vasomotion responses. The results suggest that microalbuminuria in Type 2 diabetes reflects a generalized disturbance of microvascular function related to endothelium-dependent mechanisms.
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Affiliation(s)
- Ole Schmiedel
- Diabetic Centre and Academic Unit, Maelor Hospital, University of Wales College of Medicine, Gladstone Centre, Wrexham, UK.
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Abstract
The influence of microvascular changes in diabetic foot tissue breakdown is not fully known. Research on the role of vascular mediators in diabetes and their effect on the microvasculature may help to create a more unified theory.
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Affiliation(s)
- E A Henderson
- Diabetic Foot Clinic, Sunderland Royal Hospital, Tyne and Wear, UK
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Vinik A, Parson H, Ullal J. The role of PPARs in the microvascular dysfunction in diabetes. Vascul Pharmacol 2006; 45:54-64. [PMID: 16784897 DOI: 10.1016/j.vph.2005.11.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2005] [Revised: 11/01/2005] [Accepted: 11/01/2005] [Indexed: 11/19/2022]
Abstract
There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.
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Affiliation(s)
- Aaron Vinik
- Strelitz Diabetes Institute, Eastern Virginia Medical School, Norfolk, VA 23510, United States.
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Goldfine AB, Beckman JA, Betensky RA, Devlin H, Hurley S, Varo N, Schonbeck U, Patti ME, Creager MA. Family History of Diabetes Is a Major Determinant of Endothelial Function. J Am Coll Cardiol 2006; 47:2456-61. [PMID: 16781373 DOI: 10.1016/j.jacc.2006.02.045] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2005] [Revised: 02/01/2006] [Accepted: 02/14/2006] [Indexed: 11/28/2022]
Abstract
OBJECTIVES We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. METHODS Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH-). RESULTS Although fasting glucose was higher in FH+ than FH- (5.3 +/- 0.1 mmol/l vs. 4.9 +/- 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 +/- 0.9% vs. 11.7 +/- 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH- (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04). CONCLUSIONS Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.
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Tooke JE, Elston LM, Gooding KM, Ball CI, Mawson DM, Piper J, Sriraman R, Urquhart R, Shore AC. The insulin sensitiser pioglitazone does not influence skin microcirculatory function in patients with type 2 diabetes treated with insulin. Diabetologia 2006; 49:1064-70. [PMID: 16508777 DOI: 10.1007/s00125-006-0168-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2005] [Accepted: 12/06/2005] [Indexed: 11/26/2022]
Abstract
AIMS/HYPOTHESIS Insulin resistance is associated with abnormal microvascular function. Treatment with insulin sensitisers may provoke oedema, suggesting microvascular effects. The mechanisms underlying the peripheral oedema observed during glucose-lowering treatment with thiazolidinediones are unclear. Therefore we examined the effect of pioglitazone on microvascular variables involved in oedema formation. METHODS Subjects (40-80 years) with type 2 diabetes and on insulin were randomised to 9 weeks of pioglitazone therapy (30 mg/day; n=14) or placebo (n=15). The following assessments were performed at baseline and 9 weeks: microvascular filtration capacity; isovolumetric venous pressure; capillary pressure; capillary recruitment following venous or arterial occlusion; postural vasoconstriction; and maximum blood flow. A number of haematological variables were also measured including vascular endothelium growth factor (VEGF), IL-6 and C-reactive protein (CRP). RESULTS Pioglitazone did not significantly influence any microcirculatory variable as compared with placebo (analysis of covariance [ANCOVA] for microvascular filtration capacity for the two groups, p=0.26). Mean VEGF increased with pioglitazone (61.1 pg/ml), but not significantly more than placebo (9.76 pg/ml, p=0.94). HbA(1c) levels and the inflammatory markers IL-6 and CRP decreased with pioglitazone compared with placebo (ANCOVA: p=0.009, p=0.001 and p=0.004, respectively). CONCLUSIONS/INTERPRETATION Pioglitazone improved glycaemic control and inflammatory markers over 9 weeks but had no effect on microcirculatory variables associated with oedema or insulin resistance in type 2 diabetic patients treated with insulin.
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Affiliation(s)
- J E Tooke
- Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, EX2 5AX, UK.
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Vinik AI, Ullal J, Parson HK, Barlow PM, Casellini CM. Pioglitazone treatment improves nitrosative stress in type 2 diabetes. Diabetes Care 2006; 29:869-76. [PMID: 16567830 DOI: 10.2337/diacare.29.04.06.dc05-0517] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a randomized, parallel, cross-over, double-blind, within- and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 +/- 30.8 years, HbA(1c) 7.9 +/- 00.4%, BMI 31.3 +/- 1.2 kg/m(2)). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks. RESULTS The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 +/- 1.0 vs. 2.8 +/- 0.8, P < 0.01), after local heat stimulation at 40 degrees C (12.9 +/- 2.2 vs. 5.7 +/- 1.7, P < 0.01), and after nociceptor stimulated flow with local heating at 44 degrees C (36.4 +/- 6.3 vs. 16.6 +/- 3.4). Differences were not significant in the placebo-treated group. CONCLUSIONS Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation.
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Affiliation(s)
- Aaron I Vinik
- Department of Internal Medicine, The Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, VA 23510, USA.
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Wong TY, Mohamed Q, Klein R, Couper DJ. Do retinopathy signs in non-diabetic individuals predict the subsequent risk of diabetes? Br J Ophthalmol 2006; 90:301-3. [PMID: 16488949 PMCID: PMC1856961 DOI: 10.1136/bjo.2005.084400] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND/AIMS Isolated retinopathy signs are common in non-diabetic individuals and have been shown to be associated with impaired glucose metabolism. In a cohort of people without diabetes, the association of these retinopathy signs and subsequent development of diabetes were examined. METHODS A population based cohort study of 7992 people aged 49-73 years without diabetes was conducted. Retinal photographs of these participants were evaluated for the presence of retinopathy signs according to a standardised protocol. Incident cases of diabetes were identified prospectively. RESULTS After a follow up of 3 years, 291 (3.6%) people developed incident diabetes. In the total cohort, retinopathy was not significantly associated with incident diabetes (4.7% v 3.6%, multivariable adjusted odds ratio (OR) 1.1, 95% confidence intervals (CI), 0.7 to 1.9). However, among participants with a positive family history of diabetes, retinopathy was associated with incident diabetes (10.4% v 4.8%, multivariable adjusted OR 2.3, 95% CI, 1.0 to 5.3). Among participants without a family history of diabetes, retinopathy was not associated with incident diabetes CONCLUSIONS In individuals with a family history of diabetes, retinopathy signs predict subsequent risk of clinical diabetes.
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Affiliation(s)
- T Y Wong
- Retinal Vascular Imaging Centre, Centre for Eye Research Australia, Univeristy of Melbourne, 32 Gisborne Street, VIC 3002, Australia.
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Gooding KM, Hannemann MM, Tooke JE, Clough GF, Shore AC. Maximum skin hyperaemia induced by local heating: possible mechanisms. J Vasc Res 2006; 43:270-7. [PMID: 16498265 DOI: 10.1159/000091736] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Accepted: 12/17/2005] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Maximum skin hyperaemia (MH) induced by heating skin to > or = 42 degrees C is impaired in individuals at risk of diabetes and cardiovascular disease. Interpretation of these findings is hampered by the lack of clarity of the mechanisms involved in the attainment of MH. METHODS MH was achieved by local heating of skin to 42-43 degrees C for 30 min, and assessed by laser Doppler fluximetry. Using double-blind, randomized, placebo-controlled crossover study designs, the roles of prostaglandins were investigated by inhibiting their production with aspirin and histamine, with the H1 receptor antagonist cetirizine. The nitric oxide (NO) pathway was blocked by the NO synthase inhibitor, NG-nitro-L-arginine methyl esther (L-NAME), and enhanced by sildenafil (prevents breakdown of cGMP). RESULTS MH was not altered by aspirin, cetirizine or sildenafil, but was reduced by L-NAME: median placebo 4.48 V (25th, 75th centiles: 3.71, 4.70) versus L-NAME 3.25 V (3.10, 3.80) (p = 0.008, Wilcoxon signed rank test). Inhibition of NO production (L-NAME) resulted in a more rapid reduction in hyperaemia after heating (p = 0.011), whereas hyperaemia was prolonged in the presence of sildenafil (p = 0.003). The increase in skin blood flow was largely confined to the directly heated area, suggesting that the role of heat-induced activation of the axon reflex was small. CONCLUSION NO, but not prostaglandins, histamine or an axon reflex, contributes to the increase in blood flow on heating and NO is also a component of the resolution of MH after heating.
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Affiliation(s)
- Kim M Gooding
- Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, UK
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Middlebrooke AR, Armstrong N, Welsman JR, Shore AC, Clark P, MacLeod KM. Does aerobic fitness influence microvascular function in healthy adults at risk of developing Type 2 diabetes? Diabet Med 2005; 22:483-9. [PMID: 15787677 DOI: 10.1111/j.1464-5491.2005.01455.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIM To investigate whether aerobic fitness is associated with skin microvascular function in healthy adults with an increased risk of developing Type 2 diabetes. METHODS Twenty-seven healthy normal glucose-tolerant humans with either a previous diagnosis of gestational diabetes or having two parents with Type 2 diabetes and 27 healthy adults who had no history of diabetes were recruited. Maximal oxygen uptake was assessed using an incremental exercise test to exhaustion. Skin microvascular function was assessed using laser Doppler techniques as the maximum skin hyperaemic response to a thermal stimulus (maximum hyperaemia) and the forearm skin blood flow response to the iontophoretic application of acetylcholine (ACh) and sodium nitroprusside. RESULTS Maximal oxygen uptake was not significantly different in the 'at-risk' group compared with healthy controls. Maximum hyperaemia was reduced in those 'at risk' (1.29 +/- 0.30 vs. 1.46 +/- 0.33 V, P = 0.047); however, the peak response to acetylcholine or sodium nitroprusside did not differ in the two groups. A significant positive correlation was demonstrated between maximal oxygen uptake and maximum hyperaemia (r = 0.52, P = 0.006 l/min and r = 0.60, P = 0.001 ml/kg/min) and peak ACh response (r = 0.40, P = 0.04 l/min and r = 0.47, P = 0.013 ml/kg/min) in the 'at-risk' group when expressed in absolute (l/min) or body mass-related (ml/kg/min) terms. No significant correlations were found in the control group. CONCLUSIONS In this 'at-risk' group with skin microvascular dysfunction maximal oxygen uptake was not reduced compared with healthy controls. However, in the 'at-risk' group alone, individuals with higher levels of aerobic fitness also had better microvascular and endothelial responsiveness.
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Affiliation(s)
- A R Middlebrooke
- Children's Health & Exercise Research Centre, School of Sport & Health Sciences, University of Exeter, Exeter, UK.
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Olsen MH, Fossum E, Høieggen A, Wachtell K, Hjerkinn E, Nesbitt SD, Andersen UB, Phillips RA, Gaboury CL, Ibsen H, Kjeldsen SE, Julius S. Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy. J Hypertens 2005; 23:891-8. [PMID: 15775796 DOI: 10.1097/01.hjh.0000163160.60234.15] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. METHODS In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. RESULTS Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mmHg x min x 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 l/kg x mmol x min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg x min x 100 and 12.6 versus 11.1 l/kg x mmol x min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus -14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = -0.16, P < 0.05) independently of the relative change in body mass index (r = -0.29, P < 0.001). CONCLUSIONS As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.
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Affiliation(s)
- Michael H Olsen
- Department of Clinical Physiology and Nuclear Medicine, Glostrup University Hospital, Copenhagen, Denmark.
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47
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Forst T, Lübben G, Hohberg C, Kann P, Sachara C, Gottschall V, Friedrich C, Rosskopf R, Pfützner A. Influence of Glucose Control and Improvement of Insulin Resistance on Microvascular Blood Flow and Endothelial Function in Patients with Diabetes Mellitus Type 2. Microcirculation 2005; 12:543-50. [PMID: 16207627 DOI: 10.1080/10739680500253402] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
OBJECTIVE The study was performed to investigate the effect of improving metabolic control with pioglitazone in comparison to glimepiride on microvascular function in patients with diabetes mellitus type 2. METHODS A total of 179 patients were recruited and randomly assigned to one treatment group. Metabolic control (HbA1c), insulin resistance (HOMA index), and microvascular function (laser Doppler fluxmetry) were observed at baseline and after 3 and 6 months. RESULTS HbA1c improved in both treatment arms (pioglitazone: 7.52 +/- 0.85% to 6.71 +/- 0.89%, p < .0001; glimepiride: 7.44 +/- 0.89% to 6.83 +/- 0.85%, p < .0001). Insulin-resistance decreased significantly in the pioglitazone group (6.15 +/- 4.05 to 3.85 +/- 1.92, p < .0001) and remained unchanged in the glimepiride group. The microvascular response to heat significantly improved in both treatment groups (pioglitazone 48.5 [15.2; 91.8] to 88.8 [57.6; 124.1] arbitrary units [AU], p < .0001; glimepiride 53.7 [14.1; 91.9] to 87.9 [52.9, 131.0] AU, p < .0001, median [lower and upper quartile]). Endothelial function as measured with the acetylcholine response improved in the pioglitazone group (38.5 [22.2; 68.0] to 60.2 [36.9; 82.8], p = .0427) and remained unchanged in the glimepiride group. CONCLUSIONS Improving metabolic control has beneficial effects in microvascular function in type 2 diabetic patients. Treatment of type 2 diabetic patients with pioglitazone exerts additional effects on endothelial function beyond metabolic control.
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Affiliation(s)
- Thomas Forst
- Institute for Clinical Research and Development, Mainz, Germany.
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48
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Henry RMA, Ferreira I, Kostense PJ, Dekker JM, Nijpels G, Heine RJ, Kamp O, Bouter LM, Stehouwer CDA. Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not; The Hoorn Study. Atherosclerosis 2004; 174:49-56. [PMID: 15135250 DOI: 10.1016/j.atherosclerosis.2004.01.002] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2003] [Revised: 12/09/2003] [Accepted: 01/05/2004] [Indexed: 11/26/2022]
Abstract
BACKGROUND Type 2 diabetes (DM2) and impaired glucose metabolism (IGM) are associated with an increased cardiovascular disease risk. Impaired endothelial synthesis of nitric oxide (NO) is an important feature of atherothrombosis and can be estimated from endothelium-dependent flow-mediated dilation (FMD). It is controversial whether or not FMD is impaired in DM2 and IGM. We investigated this issue in a population-based setting. METHODS AND RESULTS In the study population (n = 650; 246 with normal glucose metabolism (NGM), 135 with IGM and 269 with DM2; mean age: 67.6 years), FMD and endothelium-independent nitroglycerine-mediated dilation (NMD) were ultrasonically estimated from the brachial artery and expressed as the absolute change in diameter in mm. The increase in diameter (mean +/- standard deviation) in NGM, IGM and DM2 was 0.19 +/- 0.15, 0.19 +/- 0.18 and 0.13 +/- 0.17 MD and 0.45 +/- 0.21, 0.43 +/- 0.24 and 0.45 +/- 0.25 for NMD. After adjustment for age, sex, baseline diameter and percentage increase in peak systolic velocity, DM2, as compared to NGM, remained associated with impaired FMD (regression coefficient beta (95%CI)) as compared to NGM, -0.06 mm (-0.09 to -0.03). IGM was not associated with impaired FMD (beta, 0.01 mm (-0.02 to 0.04)). Additional adjustment for conventional cardiovascular risk factors did not alter these associations. Hyperglycemia or hyperinsulinemia explained 2% of the association between DM2 and FMD. NMD was not associated with glucose tolerance. CONCLUSIONS This study shows that DM2 is independently associated with impaired FMD. Hyperglycemia and hyperinsulinemia contribute minimally to this association. Impaired FMD may therefore, in part, explain the increased cardiovascular disease risk in DM2, whereas the normal FMD in IGM suggests that other forms of endothelial dysfunction are important in explaining the increased cardiovascular disease risk in IGM.
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Affiliation(s)
- Ronald M A Henry
- Institute for Research in Extramural Medicine, VU University Medical Center, Amsterdam, The Netherlands
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49
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Khalil OS. Non-invasive glucose measurement technologies: an update from 1999 to the dawn of the new millennium. Diabetes Technol Ther 2004; 6:660-97. [PMID: 15628820 DOI: 10.1089/dia.2004.6.660] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
There are three main issues in non-invasive (NI) glucose measurements: namely, specificity, compartmentalization of glucose values, and calibration. There has been progress in the use of near-infrared and mid-infrared spectroscopy. Recently new glucose measurement methods have been developed, exploiting the effect of glucose on erythrocyte scattering, new photoacoustic phenomenon, optical coherence tomography, thermo-optical studies on human skin, Raman spectroscopy studies, fluorescence measurements, and use of photonic crystals. In addition to optical methods, in vivo electrical impedance results have been reported. Some of these methods measure intrinsic properties of glucose; others deal with its effect on tissue or blood properties. Recent studies on skin from individuals with diabetes and its response to stimuli, skin thermo-optical response, peripheral blood flow, and red blood cell rheology in diabetes shed new light on physical and physiological changes resulting from the disease that can affect NI glucose measurements. There have been advances in understanding compartmentalization of glucose values by targeting certain regions of human tissue. Calibration of NI measurements and devices is still an open question. More studies are needed to understand the specific glucose signals and signals that are due to the effect of glucose on blood and tissue properties. These studies should be performed under normal physiological conditions and in the presence of other co-morbidities.
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Affiliation(s)
- Omar S Khalil
- Diagnostics Division, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
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50
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Mayrovitz HN, Sims N. Effects of Support Surface Relief Pressures on Heel Skin Blood Flow in Persons with and without Diabetes Mellitus. Adv Skin Wound Care 2004; 17:197-201. [PMID: 15360029 DOI: 10.1097/00129334-200405000-00019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE To investigate the effects of pressure relief magnitude on heel blood hyperemia in persons with and without diabetes mellitus. DESIGN Study participants (1 group of persons with diabetes and 1 group without diabetes) lay on a support surface for 70 minutes with 1 heel on an end cell of a support surface. Cell pressure was computer controlled to be 20 mm Hg during support and 5 or 0 mm Hg during relief. Heel skin blood perfusion was monitored by laser Doppler on the heel and foot dorsum. Heel hyperemia was determined as ratios of skin blood perfusion areas during hyperemia to preloading (AR) and peak hyperemia to mean skin blood perfusion during preload (QR). SUBJECTS 13 persons with diabetes mellitus (6 females, 7 males; age 65.2 +/- 3.0 years) and no known diabetes-related complications, and 15 persons without diabetes mellitus (7 females, 8 males; age 54.7 +/- 3.1 years) SETTING University research center. RESULTS For the nondiabetes mellitus group, hyperemia was significantly greater with complete pressure-relief compared with partial relief (P < .001). In contrast, the diabetes mellitus group showed no significantly increased response to full relief, and the hyperemia achieved during full relief, measured by AR and QR, was significantly less than with the nondiabetes mellitus group. CONCLUSIONS These results suggest that a diabetes-related reduced microvascular vasodilatory capacity is not exceeded during partial pressure relief, but is exceeded during complete pressure relief. Accordingly, differences in hyperemic response would become unmasked only when maximum hyperemia could be established during complete heel off-loading. This would suggest that a diminished hyperemia during complete off-loading, as found in the present diabetes mellitus group, may be problematic if widely present in the diabetic (or possibly older) population, under conditions in which heel loading occurs for sustained intervals.
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Affiliation(s)
- Harvey N Mayrovitz
- College of Medical Sciences, Nova Southeastern University, Ft Lauderdale, Fla, USA
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