Insulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps.
AuthorsBruce, Jason I E; orcid: 0000-0002-4503-1981; email: email@example.com
Sans, Maria Dolors; orcid: 0000-0002-9271-2106
Sugden, Sarah A
James, Andrew D; orcid: 0000-0002-2432-5948
Williams, John A
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AbstractAcute 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<sup>Akita</sup>) 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<sup>Akita</sup> 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<sup>2+</sup> ATPase (PMCA) and cytotoxic Ca<sup>2+</sup> 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.
CitationNature communications, volume 12, issue 1, page 4386
DescriptionFrom Europe PMC via Jisc Publications Router
History: ppub 2021-07-01, epub 2021-07-19
Publication status: Published
Funder: Medical Research Council; Grant(s): MR/P00251X/1
Funder: NIDDK NIH HHS; Grant(s): P30 DK089503, R01 DK059578, P30 DK020572, P60 DK020572, U2C DK110768
Funder: Wellcome Trust