Department of Cardiovascular Medicine, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Diabetologia. 2010 Dec;53(12):2676-87. doi: 10.1007/s00125-010-1887-5. Epub 2010 Sep 16.
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.
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.
Gene expression was compared with that of normoglycaemic transgenic and tamoxifen-treated wild-type 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.
目的/假设：由于低血糖或高血糖的早期影响导致的动脉不可逆损伤，可能是降低血糖治疗预防心血管疾病（CVD）事件效果有限的原因。我们假设，即使是短暂的低血糖或高血糖也会对动脉基因表达产生不利影响，而且这些变化可能无法完全逆转。
通过在β细胞中受控激活“可切换”c-Myc 转基因，使成年 pIns-c-MycER(TAM) 小鼠经历短暂的低血糖和高血糖，然后让它们恢复长达 3 个月。评估正常血糖、低血糖和高血糖再到恢复期间主动脉整体基因表达的即时和连续变化。
将基因表达与正常血糖转基因和他莫昔芬处理的野生型对照进行比较。总的来说，95 个基因的表达受到中度低血糖（血糖降至 2.5mmol/l）的显著影响，而超过 769 个基因受到高血糖的影响。激活的基因和途径包括几个与动脉粥样硬化过程相关的基因，如炎症和动脉钙化。尽管当高血糖得到纠正时（74.9%），许多基因的表达恢复到初始暴露前水平，但在四分之一的基因中并未发生这种情况。定量逆转录酶 PCR 和免疫组织化学验证了关键分子的基因表达模式，正如全局基因阵列所示。
结论/解释：短期暴露于高血糖会导致体内动脉基因表达产生有害且持久的变化。短暂的低血糖也会对基因表达产生不利影响，尽管影响较小。这些结果表明，为了避免糖尿病患者过多的 CVD 风险，可能需要早期纠正高血糖并避免低血糖。
