Department of Cardiology, Aarhus University Hospital, Skejby Sygehus, Palle Juul-Jensens Blvd. 99, 8200, Aarhus N, Denmark.
Cardiovasc Diabetol. 2017 Nov 9;16(1):148. doi: 10.1186/s12933-017-0628-1.
Hypoglycemia is associated with increased mortality rate in patients with diabetes. The underlying mechanisms may involve reduced myocardial tolerance to ischemia and reperfusion (IR) or reduced capacity for ischemic preconditioning (IPC). As IPC is associated with increased myocardial glucose uptake (MGU) during reperfusion, cardioprotection is linked to glucose metabolism possibly by O-linked β-N-acetylglucosamine (O-GlcNAc). We aimed to investigate the impact of hypoglycemia in hearts from animals with diabetes on myocardial IR tolerance, on the efficacy of IPC and whether modulations of MGU and O-GlcNAc levels are involved in the underlying mechanisms.
In a Langendorff model using diabetic ZDF (fa/fa) and non-diabetic (fa/+) rats (n = 6-7 in each group) infarct size (IS) was evaluated after 40 min of global ischemia and 120 min reperfusion during hypoglycemia [(glucose) = 3 mmol/l] and normoglycemia [(glucose) = 11 mmol/l]. Myocardial glucose uptake and O-GlcNAc levels were evaluated during reperfusion. IPC was induced by 2 × 5 min of global ischemia prior to index ischemia.
IS increased in hearts from animals with (p < 0.01) and without (p < 0.01) diabetes during hypoglycemia compared to normoglycemia. IPC reduced IS during normoglycemia in both animals with (p < 0.01) and without (p < 0.01) diabetes. During hypoglycemia, however, IPC only reduced IS in hearts from animals with diabetes (p < 0.05). IPC increased MGU during reperfusion and O-GlcNAc levels in animals with diabetes during hypo- (MGU: p < 0.05, O-GlcNAc: p < 0.05) and normoglycemia (MGU: p < 0.01, O-GlcNAc: p < 0.05) and in animals without diabetes only during normoglycemia (MGU: p < 0.05, O-GlcNAc: p < 0.01).
Hypoglycemia increases myocardial susceptibility to IR injury in hearts from animals with and without diabetes. In contrast to hearts from animals without diabetes, the hearts from animals with diabetes are amenable to cardioprotection during hypoglycemia. In parallel with IPC induced cardioprotection, MGU and O-GlcNAc levels increase suggesting that increased MGU and O-GlcNAc levels are involved in the mechanisms of IPC.
低血糖与糖尿病患者的死亡率增加有关。其潜在机制可能涉及心肌对缺血再灌注（IR）的耐受性降低或缺血预处理（IPC）能力降低。由于 IPC 与再灌注期间心肌葡萄糖摄取（MGU）增加有关，因此心脏保护可能与葡萄糖代谢有关，可能通过 O-连接的β-N-乙酰氨基葡萄糖（O-GlcNAc）。我们旨在研究低血糖对糖尿病动物心脏的 IR 耐受性、IPC 疗效的影响，以及 MGU 和 O-GlcNAc 水平的调节是否参与潜在机制。
在使用糖尿病 ZDF（fa/fa）和非糖尿病（fa/+）大鼠的 Langendorff 模型中（每组 n=6-7），在低血糖[（葡萄糖）= 3mmol/l]和正常血糖[（葡萄糖）= 11mmol/l]下，评估 40min 全缺血和 120min 再灌注后的梗死面积（IS）。在再灌注期间评估心肌葡萄糖摄取和 O-GlcNAc 水平。在指数缺血前进行 2×5min 的全缺血以诱导 IPC。
与正常血糖相比，糖尿病动物（p<0.01）和非糖尿病动物（p<0.01）的心脏在低血糖时 IS 增加。在正常血糖下，IPC 降低了糖尿病动物（p<0.01）和非糖尿病动物（p<0.01）的 IS。然而，在低血糖期间，IPC 仅降低了糖尿病动物的 IS（p<0.05）。IPC 在低血糖（MGU：p<0.05，O-GlcNAc：p<0.05）和正常血糖（MGU：p<0.01，O-GlcNAc：p<0.05）期间增加了糖尿病动物的 MGU 和 O-GlcNAc 水平，而仅在正常血糖下增加了非糖尿病动物的 MGU 和 O-GlcNAc 水平（MGU：p<0.05，O-GlcNAc：p<0.01）。
低血糖增加了糖尿病和非糖尿病动物心脏对 IR 损伤的敏感性。与非糖尿病动物的心脏相反，糖尿病动物的心脏在低血糖时容易受到心脏保护。与 IPC 诱导的心脏保护平行，MGU 和 O-GlcNAc 水平增加，表明增加的 MGU 和 O-GlcNAc 水平参与了 IPC 的机制。
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