Fig. 10: Cartoon depicting the putative molecular mechanism for insulin protection of pancreatic acinar cells during acute pancreatitis.

Pancreatitis inducing agents, such as fatty acid/ethanol metabolite palmitoleic acid (POA) impair metabolism, most notably mitochondrial function, leading to ATP depletion and inhibition of Ca²⁺ clearance pathways, such as the plasma membrane Ca²⁺ ATPase (PMCA), leading to cytotoxic Ca²⁺ overload. The net effect of ATP depletion and cytotoxic Ca²⁺ overload is rapid necrotic cell death, a major hallmark of acute pancreatitis. Insulin binding to the insulin receptor leads to the downstream activation of the PI3K/Akt signalling pathway and the direct Akt-mediated phosphorylation and activation of the key glycolytic enzyme, phosphofructokinase fructose bisphosphatase-2 (PFKFB2). This leads to the production of the key glycolytic metabolite fructose 2,6-bisphosphate, which is an allosteric activator of the rate limiting phosphofructokinase-1 (PFK1), which in turn drives glycolytic flux and thus glycolytic ATP production and supply to the PMCA. This appears to be sufficient to maintain acinar cell ATP and prevent inhibition of the PMCA, even in the face of impaired mitochondrial function, thereby protecting against necrotic cell death and the self-perpetuating tissue injury and spiralling inflammatory response characteristic of acute pancreatitis. During diabetes (Ins2^Akita mice) and in PACIRKO mice, this endogenous insulin protection is abolished, leading to more severe acute pancreatitis. Moreover, exogenous insulin administration, using the hyperinsulinaemic euglycaemic clamp to infuse high dose insulin while maintaining close glucose control, ameliorates or protects against further pancreatic injury suggesting a potential therapy for severe acute pancreatitis.