Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans

Ahmed Iqbal, Lynne R. Prince, Peter Novodvorsky, Alan Bernjak, Mark R. Thomas, Lewis Birch, Danielle Lambert, Linda J. Kay, Fiona J. Wright, Ian A. Macdonald, Richard M. Jacques, Robert F. Storey, Rory J. McCrimmon, Sheila Francis, Simon R. Heller (Lead / Corresponding author), Ian Sabroe

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    Abstract

    Context: Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk.

    Objective: To determine whether hypoglycemia modifies subsequent innate immune system responses.

    Design and Setting: Single-blinded, prospective study of three independent parallel groups.

    Participants and Interventions: Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/l), euglycemic (6.0 mmol/l) or sham-saline clamp (n=8 for each group). Forty-eight hours later, all participants received low-dose (0.3 ng/kg) intravenous endotoxin.

    Main outcome measures: We studied in-vivo monocyte mobilization and monocyte-platelet interactions.

    Results: Hypoglycemia increased total leucocytes (9.98±1.14 x109/l vs euglycemia: 4.38±0.53 x109/l; P<0.001 vs sham-saline: 4.76±0.36 x109/l; P<0.001) (mean±SEM), mobilized proinflammatory intermediate monocytes (42.20±7.52/μl vs euglycemia: 20.66±3.43/μl; P<0.01 vs sham-saline: 26.20±3.86/μl; P<0.05) and non-classical monocytes (36.16±4.66/μl vs euglycemia: 12.72±2.42/μl; P<0.001 vs sham-saline: 19.05±3.81/μl; P<0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (AUC) increased (73.87±7.30 vs 52.50±4.04; P<0.05) and formation of monocyte-platelet aggregates increased (96.05±14.51/μl vs 49.32±6.41/μl; P<0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51±1.42/μl vs euglycemia: 4.19±1.08/μl; P<0.05 vs sham-saline: 3.81±1.42/μl; P<0.05) and non-classical monocytes (9.53±1.08/μl vs euglycemia: 2.86±0.72/μl; P<0.01 vs sham-saline: 3.08±1.01/μl; P<0.05) with platelets compared to controls. Hypoglycemia led to greater leucocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96±0.97 vs euglycemia: 8.21±0.85 x109/l; P<0.05).

    Conclusions: Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute towards increased cardiovascular risk observed in people with diabetes.

    Original languageEnglish
    Pages (from-to)1187-1199
    Number of pages13
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume104
    Issue number4
    Early online date24 Sep 2018
    DOIs
    Publication statusPublished - Apr 2019

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    Iqbal, A., Prince, L. R., Novodvorsky, P., Bernjak, A., Thomas, M. R., Birch, L., Lambert, D., Kay, L. J., Wright, F. J., Macdonald, I. A., Jacques, R. M., Storey, R. F., McCrimmon, R. J., Francis, S., Heller, S. R., & Sabroe, I. (2019). Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans. Journal of Clinical Endocrinology and Metabolism, 104(4), 1187-1199. https://doi.org/10.1210/jc.2018-01168