Repetitive hypoglycaemia increases serum adrenaline and induces monocyte adhesion to the endothelium in rat thoracic aorta

Abstract

Aims/hypothesis Severe hypoglycaemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect and mechanism of hypoglycaemia on the progression of atherosclerosis remains largely unknown. As a first step towards elucidating the above, we investigated the effect of hypoglycaemia on monocyte-endothelial interaction. Methods Insulin was injected intraperitoneally once every 3 days for 5 weeks in Goto-Kakizaki rats, a non-obese rat model of type 2 diabetes. We counted the number of monocytes adherent to the endothelium of thoracic aorta as an index of early atherosclerogenesis. Cultured HUVEC were used to investigate the mechanism of action. Results Insulin treatment increased the number of monocytes adherent to the vascular endothelium. This increase was abrogated by injection of glucose with insulin. Amosulalol, an α-1 and β-adrenoreceptor antagonist, suppressed monocyte adhesion to endothelium and levels of adhesion molecules (intercellular adhesion molecule-1 and vascular cell adhesion molecule-1) in the endothelial surface, which had been enhanced by insulin-induced hypoglycaemia. In HUVEC, adrenaline (epinephrine) significantly increased nuclear translocation of nuclear factor-κB (NF-κB) p65 and levels of adhesion molecules, effects that were abrogated following addition of SQ22536, a specific adenyl cyclase inhibitor. Conclusions/interpretation Our data indicate that repetitive hypoglycaemia induced by insulin enhanced monocyte adhesion to endothelial cells in Goto-Kakizaki rat aorta through enhanced adrenaline activity and that the latter stimulated intracellular cAMP, leading to nuclear translocation of NF-κB with subsequent production of adhesion molecules in endothelial cells.

Hypoglycemia and risk of vascular events and mortality: a systematic review and meta-analysis

“…Subsequent to hypoglycemia, the counter-regulatory hormonal response [51] may lead to progression of atherosclerosis, amplified platelet activation, leukocyte mobilization, and coagulation [52][53][54], which may further trigger cardiovascular disease events. Furthermore, with the increase in catecholamine release, hypoglycemia has also been associated with marked hemodynamic perturbations [18], cardiac arrhythmia [19,20], and aggravated cardiac and cerebral ischemia [22].…”

Severe hypoglycaemia and cardiovascular disease: systematic review and meta-analysis with bias analysis

“…11 The increase in catecholamine also leads to platelet activation, leucocyte mobilisation, and coagulation, 12 which may trigger cardiovascular disease events. Inflammation and endothelial dysfunction are also induced by acute hypoglycaemia, 13 and both play roles in the development of atherosclerosis. Furthermore, cardiac ischaemia or fatal arrhythmia during hypoglycaemia may lead to cardiovascular disease.…”

“…[8][9][10] If severe hypoglycaemia induces cardiovascular disease events, it may also dilute the potential benefit of intensive glucose control on such events because intensive glucose control increases the risk of severe hypoglycaemia. 3 This is biologically plausible because severe hypoglycaemia has acute effects on sympathoadrenal activation, 11 inflammation, 12 and endothelial function, 13 all of which have potential adverse cardiovascular effects. In addition, cardiac ischaemia or fatal arrhythmia during hypoglycaemia may be responsible for the increased risk of cardiovascular disease among patients with severe hypoglycaemia.…”

Glycated Albumin to Glycated Hemoglobin Ratio is a Sensitive Indicator of Blood Glucose Variability in Patients with Fulminant Type 1 Diabetes

“…Recently, it has been suggested that the progression of macroangiopathies is related to the level of postprandial hyperglycemia and glycemic variability (5)(6)(7)(8). Repetitive hypoglycemia also had several adverse effects in the development of atherosclerosis (9). As HbA1c may not be a sensitive marker of glycemic fluctuation (10), a specific surrogate marker that better reflects glycemic variance is needed in clinical practice.…”