Hypoglycemia increases inflammatory reactions, cardiovascular risk
Hypoglycemia may often be under appreciated for its clinical significance in complex chronic disorders. Known to promote surges of inflammation in autoimmune disorders, is shown to increase the inflammatory reaction to endotoxin (LPS, the lipopolysaccharide component of bacterial outer membranes). A study just published in the Journal of Clinical Endocrinology & Metabolism offers evidence that this increases the risk for cardiovascular disease—disorders characterized by vascular inflammation. The authors state:
"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."
They further note:
"In large prospective studies, CV events did not appear to occur during the hypoglycemic episode per se but there was an increased risk of events in the weeks and months following the episode. We hypothesized, therefore, that acute hypoglycemia may prime the innate immune system, leading to a more pronounced inflammatory response to a subsequent inflammatory stimulus downstream from the initial episode of hypoglycemia."
They went about determining if low blood glucose can modify subsequent immune system responses by exposing three study cohorts to intravenous endotoxin (LPS, an immune system activator) after either a hyperinsulinemic-hypoglycemic, euglycemic or sham-saline clamp. They then observed in-vivo monocyte mobilization and monocyte-platelet interactions. This has widespread clinical significance since it is common for the immune system to be exposed to LPS in the gut (and LPS is used as an adjuvant in vaccines).
Hypoglycemia increases the inflammatory response to LPS
The hypoglycemic state markedly increased biomarkers of immune system reactivity.
"Hypoglycemia increased total leucocytes...mobilized proinflammatory intermediate monocytes and non-classical monocytes...Following hypoglycemia vs euglycemia, platelet aggregation to agonist (AUC) increased and formation of monocyte-platelet aggregates increased. Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes...and non-classical monocytes...with platelets compared to controls. Hypoglycemia led to greater leucocyte mobilization in response to subsequent low-dose endotoxin challenge."
Low blood glucose increases cardiovascular risk
On the basis of their data the authors assert:
"Hypoglycemia may contribute to exacerbations of ischemic CV disease...Our main findings were: (1) hypoglycemia increased the number of all three circulating monocyte subsets, in association with a stress response characterized by increased plasma epinephrine levels; (2) hypoglycemia increased platelet reactivity, promoted formation of MPAs and promoted aggregate formation between proinflammatory monocytes and platelets; (3) leucocyte mobilization to the stress response of low-dose endotoxin was independent of epinephrine, and antecedent hypoglycemia resulted in a significantly higher inflammatory leucocyte response to low-dose endotoxin administered 48 hours later."
Note that the authors' specific focus was on the cardiovascular consequences of low blood glucose in the diabetic population whose medications may provoke hypoglycemic episodes. But clinicians should be alert to the inflammatory effects of hypoglycemia for any complex chronic condition.The authors conclude:
"...hypoglycemia mobilized proatherogenic monocyte subsets and induced prothrombotic changes by increasing platelet reactivity. In addition, hypoglycemia amplified interactions between platelets and monocytes by promoting MPA formation with enhanced aggregation of proinflammatory monocytes with platelets. Hypoglycemia may also prime the innate immune system to respond more robustly to stimuli such as endotoxin. This implies proinflammatory consequences of hypoglycemia beyond the acute episode. These data provide novel mechanistic insights into how hypoglycemia could increase CV risk through upregulation of inflammatory responses."
Readers may also be interested in Quercetin may protect against LPS-induced inflammation.