Dataset Information

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). After 48 hours, 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 leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/?L vs euglycemia 20.66 ± 3.43/?L, P < 0.01; vs sham-saline 26.20 ± 3.86/?L, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/?L vs euglycemia 12.72 ± 2.42/?L, P < 0.001; vs sham-saline 19.05 ± 3.81/?L, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/?L vs 49.32 ± 6.41/?L, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/?L vs euglycemia 4.19 ± 1.08/?L, P < 0.05; vs sham-saline 3.81± 1.42/?L, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/?L vs euglycemia 2.86 ± 0.72/?L, P < 0.01; vs sham-saline 3.08 ± 1.01/?L, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/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 to increased cardiovascular risk observed in people with diabetes.

SUBMITTER: Iqbal A

PROVIDER: S-EPMC6391720 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Iqbal Ahmed A Prince Lynne R LR Novodvorsky Peter P Bernjak Alan A Thomas Mark R MR Birch Lewis L Lambert Danielle D Kay Linda J LJ Wright Fiona J FJ Macdonald Ian A IA Jacques Richard M RM Storey Robert F RF McCrimmon Rory J RJ Francis Sheila S Heller Simon R SR Sabroe Ian I

The Journal of clinical endocrinology and metabolism 20190401 4

<h4>Context</h4>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.<h4>Objective</h4>To determine whether hypoglycemia modifies subsequent innate immune system responses.<h4>Design and setting</h4>Single-blinded, prospective study of three independent parallel groups.<h4>Participants and interventions</h4>Twenty-four healthy participants underwent either a h ...[more]

PMID: 30252067

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Project description:Data conflict with regard to whether peroxisome proliferator-activated receptor-? agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-? agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation.In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m(2), 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily. After 6 to 8 weeks of treatment, subjects underwent a low-dose LPS challenge. Clinical and blood measurements were collected at randomization, before LPS administration, and serially for 24 hours after LPS administration. We examined area under the curve for evoked responses by treatment group. Compared to placebo, but before LPS challenge, fenofibrate reduced total cholesterol and tended to decrease triglycerides, consistent with achieved therapeutic plasma levels of fenofibric acid. In the placebo group, LPS induced a modest inflammatory response with increased cytokines and chemokines (2- to 4-hour post-LPS 8-fold increase in tumor necrosis factor-?, 9-fold increase in interleukin-6, 9-fold increase in interleukin-10, and 10-fold increase in monocyte chemotactic protein-1; all P<0.001) and acute-phase reactants (24-hour post-LPS 15-fold increase in serum amyloid A and 9-fold increase in C-reactive protein; both P<0.001). Compared to placebo, however, fenofibrate did not significantly attenuate LPS-induced levels of plasma cytokines, chemokines, or acute-phase proteins.These data suggest a lack of systemic antiinflammatory properties of fenofibrate at clinically relevant dosing in humans.URL: http://clinicaltrials.gov/ct2/show/NCT01048502. Unique identifier: NCT01048502. (J Am Heart Assoc. 2012;1:e002923 doi: 10.1161/JAHA.112.002923.).

Dataset Information

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

Context

Objective

Design and setting

Participants and interventions

Main outcome measures

Results

Conclusions

Publications

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

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