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      Effects of Acute Hypoglycemia on Inflammatory and Pro-atherothrombotic Biomarkers in Individuals With Type 1 Diabetes and Healthy Individuals

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          Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals.


          Thirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m 2, A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m 2, A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg −1 · min −1) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study.


          Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased ( P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes.


          In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

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          Most cited references 19

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          Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia.

          To determine the frequency of hypoglycemia in patients with type I diabetes and impaired awareness of hypoglycemia by prospective assessment. A prospective study was undertaken for 12 months in 60 patients with type I diabetes: 29 had impaired awareness of hypoglycemia and 31 retained normal awareness of hypoglycemia. The two groups of patients were matched for age, age at onset of diabetes, duration of diabetes, and glycemic control. Episodes of severe hypoglycemia were recorded within 24 h of the event and verified where possible by witnesses. During the 12 months, 19 (66%) of the patients with impaired awareness had one or more episodes of severe hypoglycemia with an overall incidence of 2.8 episodes.patient-1.year-1. By comparison, 8 (26%) of the patients with normal awareness experienced severe hypoglycemia (P < 0.01) with an annual incidence of 0.5 episode.patient-1.year-1 (P < 0.001). Severe hypoglycemia occurred at different times of the day in the two groups: patients with impaired awareness experienced a greater proportion of episodes during the evening (P = 0.03), and patients with normal awareness experienced a greater proportion in the early morning (P = 0.05). An assessment of fear of hypoglycemia revealed that patients with impaired awareness of hypoglycemia worried more about hypoglycemia than did patients with normal awareness (P = 0.008), but did not modify their behavior accordingly. This prospective evaluation demonstrated that impaired awareness of hypoglycemia predisposes to a sixfold increase in the frequency of severe hypoglycemia, much of which occurred at home during waking hours.
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            The value of cardiovascular autonomic function tests: 10 years experience in diabetes.

             D Ewing,  C Martyn,  R. Young (2015)
            Five simple, noninvasive cardiovascular reflex tests have been used to assess autonomic function in one center over the past 10 yr. Seven hundred seventy-four diabetic subjects were tested for diagnostic and research purposes. In 543 subjects completing all five tests, abnormalities of heart rate tests occurred in 40%, while abnormal blood pressure tests occurred in less than 20%. Their results were grouped as normal (39%), early (15%), definite (18%), and severe (22%) involvement. Six percent had an atypical pattern of results. Two hundred thirty-seven diabetic subjects had the tests repeated greater than or equal to 3 mo apart: 26% worsened, 71% were unchanged, and only 3% improved. The worsening followed a sequential pattern with first heart rate and later additional blood pressure abnormalities. Comparison between a single test (heart rate response to deep breathing) and the full battery in 360 subjects showed that one test alone does not distinguish the degree or severity of autonomic damage. These tests provide a useful framework to assess autonomic neuropathy simply, quickly, and noninvasively.
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              Vascular endothelial growth factor enhances atherosclerotic plaque progression.

              Vascular endothelial growth factor (VEGF) can promote angiogenesis but may also exert certain effects to alter the rate of atherosclerotic plaque development. To evaluate this potential impact on plaque progression, we treated cholesterol-fed mice doubly deficient in apolipoprotein E/apolipoprotein B100 with low doses of VEGF (2 microg/kg) or albumin. VEGF significantly increased macrophage levels in bone marrow and peripheral blood and increased plaque area 5-, 14- and 4-fold compared with controls at weeks 1, 2 and 3, respectively. Plaque macrophage and endothelial cell content also increased disproportionately over controls. In order to confirm that the VEGF-mediated plaque progression was not species-specific, the experiment was repeated in cholesterol-fed rabbits at the three-week timepoint, which showed comparable increases in plaque progression.

                Author and article information

                Diabetes Care
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                July 2010
                : 33
                : 7
                : 1529-1535
                1University of Maryland School of Medicine, Baltimore, Maryland;
                2Department of Diabetes, Endocrinology, and Metabolism, Vanderbilt University, Nashville, Tennessee.
                Author notes
                Corresponding author: Stephen N. Davis, sdavis@ 123456medicine.umaryland.edu .
                © 2010 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                Funded by: National Institutes of Health
                Award ID: P50-HL-081009
                Award ID: R01-DK-069803
                Award ID: MO1-RR-000095
                Award ID: P01-HL-056693
                Award ID: P60-DK-020593
                Original Research

                Endocrinology & Diabetes


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