Insulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps.
Insulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps.
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DOI：
10.1038/s41467-021-24506-w
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发表时间：
2021-07-19
影响因子：
16.6
通讯作者：
Williams JA
中科院分区：
文献类型：
--
作者：
Bruce JIE;Sánchez-Alvarez R;Sans MD;Sugden SA;Qi N;James AD;Williams JA
急性胰腺炎（AP）是胰腺的严重炎症性疾病。越来越多的证据表明糖尿病与急性胰腺炎的严重程度有关，这表明内源性胰岛素可能具有保护作用。我们在糖尿病小鼠（Ins2Akita）和胰腺腺泡细胞特异性条件胰岛素受体敲除小鼠（PACIRKO）的AP细胞和体内模型中研究了胰岛素的这种假定的保护作用。与对照小鼠相比，in2akita和PACIRKO小鼠的毛豆蛋白和棕榈油酸/乙醇诱导的胰腺炎更严重，这表明内源性胰岛素在体内直接保护腺泡细胞。在分离的胰腺腺泡细胞中，胰岛素诱导akt介导的6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶2 （PFKFB2）磷酸化，从而上调糖酵解，从而防止poa诱导的ATP消耗，抑制ATP依赖的质膜Ca2+ ATP酶（PMCA）和细胞毒性Ca2+过载。这些数据提供了糖尿病与AP严重程度之间的第一个机制联系，并提示PFKFB2的磷酸化可能代表了治疗AP的潜在治疗策略。急性胰腺炎是一种严重的炎症性疾病，在糖尿病小鼠中更为严重。在这里，作者使用缺乏胰腺腺泡细胞胰岛素受体的小鼠来证明这可能是因为胰岛素在胰腺炎期间保留了腺泡细胞的糖酵解能量供应，从而防止细胞毒性钙超载和细胞死亡。
Acute pancreatitis (AP) is serious inflammatory disease of the pancreas. Accumulating evidence links diabetes with severity of AP, suggesting that endogenous insulin may be protective. We investigated this putative protective effect of insulin during cellular and in vivo models of AP in diabetic mice (Ins2Akita) and Pancreatic Acinar cell-specific Conditional Insulin Receptor Knock Out mice (PACIRKO). Caerulein and palmitoleic acid (POA)/ethanol-induced pancreatitis was more severe in both Ins2Akita and PACIRKO vs control mice, suggesting that endogenous insulin directly protects acinar cells in vivo. In isolated pancreatic acinar cells, insulin induced Akt-mediated phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2) which upregulated glycolysis thereby preventing POA-induced ATP depletion, inhibition of the ATP-dependent plasma membrane Ca2+ ATPase (PMCA) and cytotoxic Ca2+ overload. These data provide the first mechanistic link between diabetes and severity of AP and suggest that phosphorylation of PFKFB2 may represent a potential therapeutic strategy for treatment of AP. Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.
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影响因子：
14.6
作者：
Griesdale, Donald E. G.;de Souza, Russell J.;Talmor, Daniel
通讯作者：
Talmor, Daniel
影响因子：
4.5
作者：
DANIELSSON, A
通讯作者：
DANIELSSON, A
DOI：
10.1152/ajpgi.00525.2003
发表时间：
2004-07-01
影响因子：
4.5
作者：
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通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
4.7
作者：
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通讯作者：
Martinez-Outschoorn UE