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; Ian Sabroe

doi:10.1210/jc.2018-01168

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 language	English
Pages (from-to)	1187-1199
Number of pages	13
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	104
Issue number	4
Early online date	24 Sept 2018
DOIs	https://doi.org/10.1210/jc.2018-01168
Publication status	Published - Apr 2019

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McCrimmon, Rory
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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

@article{072957d98d584188ab932d92defaa56e,

title = "Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans",

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.",

author = "Ahmed Iqbal and Prince, {Lynne R.} and Peter Novodvorsky and Alan Bernjak and Thomas, {Mark R.} and Lewis Birch and Danielle Lambert and Kay, {Linda J.} and Wright, {Fiona J.} and Macdonald, {Ian A.} and Jacques, {Richard M.} and Storey, {Robert F.} and McCrimmon, {Rory J.} and Sheila Francis and Heller, {Simon R.} and Ian Sabroe",

note = "Funding: MRC Clinical Research Training Fellowship (R/139602-11-1) awarded to Dr Ahmed Iqbal.",

year = "2019",

month = apr,

doi = "10.1210/jc.2018-01168",

language = "English",

volume = "104",

pages = "1187--1199",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "4",

}

Iqbal, A, Prince, LR, Novodvorsky, P, Bernjak, A, Thomas, MR, Birch, L, Lambert, D, Kay, LJ, Wright, FJ, Macdonald, IA, Jacques, RM, Storey, RF, McCrimmon, RJ, Francis, S, Heller, SR & Sabroe, I 2019, 'Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 4, pp. 1187-1199. https://doi.org/10.1210/jc.2018-01168

TY - JOUR

T1 - Effect of Hypoglycemia on Inflammatory Responses and the Response to Low Dose Endotoxemia in Humans

AU - Iqbal, Ahmed

AU - Prince, Lynne R.

AU - Novodvorsky, Peter

AU - Bernjak, Alan

AU - Thomas, Mark R.

AU - Birch, Lewis

AU - Lambert, Danielle

AU - Kay, Linda J.

AU - Wright, Fiona J.

AU - Macdonald, Ian A.

AU - Jacques, Richard M.

AU - Storey, Robert F.

AU - McCrimmon, Rory J.

AU - Francis, Sheila

AU - Heller, Simon R.

AU - Sabroe, Ian

N1 - Funding: MRC Clinical Research Training Fellowship (R/139602-11-1) awarded to Dr Ahmed Iqbal.

PY - 2019/4

Y1 - 2019/4

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2018-01168

DO - 10.1210/jc.2018-01168

M3 - Article

C2 - 30252067

SN - 0021-972X

VL - 104

SP - 1187

EP - 1199

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 4

ER -

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

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