Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Nat Commun. 2021 Jul 19;12(1):4386. doi: 10.1038/s41467-021-24506-w.
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 (Ins2) 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 Ins2 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 Ca ATPase (PMCA) and cytotoxic Ca 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.
急性胰腺炎（AP）是一种严重的胰腺炎症性疾病。越来越多的证据表明糖尿病与 AP 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（Ins2）和胰腺腺泡细胞特异性条件性胰岛素受体敲除小鼠（PACIRKO）的细胞和体内 AP 模型中研究了胰岛素的这种潜在保护作用。与对照小鼠相比，在 Ins2 和 PACIRKO 中，钙调蛋白和棕榈油酸（POA）/乙醇诱导的胰腺炎更严重，这表明内源性胰岛素可直接在体内保护腺泡细胞。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-2,6-二磷酸酶 2（PFKFB2）磷酸化，从而上调糖酵解，防止 POA 诱导的 ATP 耗竭、抑制 ATP 依赖性质膜 Ca ATP 酶（PMCA）和细胞毒性 Ca 过载。这些数据首次在糖尿病和 AP 严重程度之间建立了机制联系，并表明 PFKFB2 的磷酸化可能代表治疗 AP 的潜在治疗策略。
