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Prolonged Prothrombotic Effects of Antecedent Hypoglycemia in Individuals With Type 2 Diabetes
Abstract
OBJECTIVE: Hypoglycemia has been linked to persistent increases in cardiovascular (CV) mortality in type 2 diabetes after the event. Our aim was to examine acute and downstream effects of hypoglycemia on markers of thrombosis risk and inflammation in type 2 diabetes. RESEARCH DESIGN AND METHODS: Twelve individuals with type 2 diabetes with no history of CV disease and 11 age- and BMI-matched volunteers without diabetes underwent paired hyperinsulinemic-euglycemic (glucose 6 mmol/L for two 60-min periods) and hypoglycemic (glucose 2.5 mmol/L for two 60-min periods) clamps on separate occasions on day 0. Fibrin clot properties, platelet reactivity, and inflammatory markers were measured at baseline, end of and after recovery from the initial clamp, day 1, and day 7 using validated assays and electron microscopy. RESULTS: Euglycemic hyperinsulinemia reduced platelet reactivity, decreased fibrin clot density, and improved fibrinolytic efficiency in both groups. Platelet reactivity and aggregation increased during acute hypoglycemia in both groups, resolving at recovery. In type 2 diabetes, clot lysis times and clot maximum absorbance increased up to day 7 (P = 0.002 and 0.001 vs. euglycemia, respectively), but clots from control subjects without diabetes showed limited changes. Fibrin network density increased Δ 1.15 ± 0.28 fibers/μm2 at day 7 after the hypoglycemic clamp (P < 0.01 for glycemic arm), whereas fibrinogen and complement C3 increased after hypoglycemia up to day 7 in type 2 diabetes only. CONCLUSIONS: Antecedent hypoglycemia has acute and persistent prothrombotic effects, lasting at least 7 days, that were enhanced in individuals with type 2 diabetes. These findings identify mechanisms by which hypoglycemia might increase short- and medium-term risk of CV mortality.
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“Additionally, hypoglycemia can produce endothelial dysfunction (increased atherothrombosis, decreased fibrinolytic balance, reduced nitric oxide) and a prothrombotic state that has been shown to persist to at least 7 days after antecedent hypoglycemia”
From Stress, hypoglycemia, and the autonomic nervous system (2022) · cites this paper as Chow et al., 2018
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Physiology and immunology of the cholinergic antiinflammatory pathway
Tracey, K. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30555 · Cited by 1,563 · cited 1×
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BackgroundSevere hypoglycemia and risks of vascular events and death
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Cited by
Amiel, S. A., Aschner, P., Childs, B., Cryer, P. E., de Galan, B. E., Frier, B. M., Gonder-Frederick, L., Heller, S. R., Jones, T., Khunti, K., et al. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(18)30315-2 · Cited by 526
Self-citationLake, A., Arthur, A., Byrne, C., Davenport, K., Yamamoto, J. M., & Murphy, H. R. (2019) · Diabetic Medicine · doi:10.1111/dme.14115 · Cited by 57
Ajjan, R. A., Heller, S. R., Everett, C. C., Vargas-Palacios, A., Higham, R., Sharples, L., Gorog, D. A., Rogers, A., Reynolds, C., Fernandez, C., et al. (2023) · Diabetes Care · doi:10.2337/dc22-1219 · Cited by 44
Self-citationStress, hypoglycemia, and the autonomic nervous system
Haas, A., Borsook, D., Adler, G., & Freeman, R. (2022) · Autonomic Neuroscience · doi:10.1016/j.autneu.2022.102983 · Cited by 30
Metadata
- Authors
- Chow, E., Iqbal, A., Walkinshaw, E., Phoenix, F., Macdonald, I. A., Storey, R. F., Ajjan, R., & Heller, S. R.
- Affiliations
- Department of Infection Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, U.K.
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, U.K.
- Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, U.K.
- School of Life Sciences, University of Nottingham, Nottingham, U.K.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2018-10-16
- Volume
- 41
- Issue
- 12
- Pages
- 2625-2633
- ISSN
- 0149-5992
- 1935-5548
- Cited by
- 63
- References
- 7
- Language
- en
- Funders
- National Institute for Health Research (NIHR) Biomedical Research Fellowship, U.K (BRF-2011-004)
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