Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully ‘switchable’ in vivo mouse model of diabetes

Abstract

Aims/hypothesis Irreversible arterial damage due to early effects of hypo-or hyperglycaemia could account for the limited success of glucose-lowering treatments in preventing cardiovascular disease (CVD) events. We hypothesised that even brief hypo-or hyperglycaemia could adversely affect arterial gene expression and that these changes, moreover, might not be fully reversible. Methods By controlled activation of a 'switchable' c-Myc transgene in beta cells, adult pIns-c-MycER TAM mice were rendered transiently hypo-and then hyperglycaemic, after which they were allowed to recover for up to 3 months. Immediate and sequential changes in aortic global gene expression from normal glycaemia through hypo-and hyperglycaemia to recovery were assessed. Results Gene expression was compared with that of normoglycaemic transgenic and tamoxifen-treated wildtype controls. Overall, expression of 95 genes was significantly affected by moderate hypoglycaemia (glucose down to 2.5 mmol/l), whereas over 769 genes were affected by hyperglycaemia. Genes and pathways activated included several involved in atherogenic processes, such as inflammation and arterial calcification. Although expression of many genes recovered to initial pre-exposure levels when hyperglycaemia was corrected (74.9%), in one in four genes this did not occur. Quantitative reverse transcriptase PCR and immunohistochemistry verified the gene expression patterns of key molecules, as shown by global gene arrays. Conclusions/interpretation Short-term exposure to hyperglycaemia can cause deleterious and persistent changes in arterial gene expression in vivo. Brief hypoglycaemia also adversely affects gene expression, although less substantially. Together, these results suggest that early correction of hyperglycaemia and avoidance of hypoglycaemia may both be necessary to avoid excess CVD risk in diabetes.

Glucose Variability: How Does It Work?

“…These genes were involved in atherogenic processes, including inflammation and arterial calcification. Although the expression of many genes returned to its initial level after 3 months, in one in four genes, recovery was not observed [160]. These data indicate that non-physiological glucose fluctuations may have a prolonged effect on gene expression.…”

Cardiac implications of hypoglycaemia in patients with diabetes – a systematic review

“…Moreover, it was suggested that brief hypoglycaemia could irreversibly affect atrial gene expression favouring CV risk [83]. …”

2013 Russell Ross Memorial Lecture in Vascular Biology

“…Other studies demonstrate that hyperglycemia causes changes in aortic gene expression, including in genes involved in inflammation and calcification, in a non-atherosclerotic mouse model. 60 Another approach to evaluate the role of increased glucose metabolism in SMCs is to overexpress the glucose transporter GLUT1. Targeted overexpression of GLUT1 in SMCs leads to increased vascular inflammation, as assessed by an increased number of neutrophils and increased CCL2 levels in a balloon injury model in non-atherosclerotic mice.…”