Abstract
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.
Highlights
Acute pancreatitis (AP) is serious inflammatory disease of the pancreas
To test whether endogenous insulin had any protective effect during AP, we first induced experimental pancreatitis in parallel groups of agematched type-1 diabetic Ins2Akita mice vs control C57BL/6 wildtype mice (WT)
Impaired insulin secretion and deletion of insulin receptors (IRs) in pancreatic acinar cells both led to worse pancreatitis
Summary
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. 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. This is sufficient to drive glycolytic flux and maintain the glycolytic ATP supply to the plasma membrane Ca2+ pumps (PMCA), thereby preventing cytotoxic Ca2+ overload and necrotic cell death even in the face of impaired mitochondrial function This provides a strong mechanistic link between diabetes and the severity of acute pancreatitis and suggests that the phosphorylation of PFKFB2, by insulin or insulin-mimetics, and the preservation of acinar cell ATP, may represent a potential therapeutic strategy for the treatment of AP
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