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

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.

To determine whether hypoglycemia modifies subsequent innate immune system responses.

Single-blinded, prospective study of three independent parallel groups.

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.

We studied in-vivo monocyte mobilization and monocyte-platelet interactions.

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/microL vs euglycemia 20.66 ± 3.43/microL, P < 0.01; vs sham-saline 26.20 ± 3.86/microL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/microL vs euglycemia 12.72 ± 2.42/microL, P < 0.001; vs sham-saline 19.05 ± 3.81/microL, 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/microL vs 49.32 ± 6.41/microL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/microL vs euglycemia 4.19 ± 1.08/microL, P < 0.05; vs sham-saline 3.81± 1.42/microL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/microL vs euglycemia 2.86 ± 0.72/microL, P < 0.01; vs sham-saline 3.08 ± 1.01/microL, 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).

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.