Abstract

BackgroundType 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. The recent finding that PaC incidence increases linearly with increasing fasting glucose levels supports a central role for hyperglycaemia, which is known to cause carbonyl stress and advanced glycation end-product (AGE) accumulation through increased glycolytic activity and non-enzymatic reactions. This study investigated the impact of hyperglycaemia on invasive tumour development and the underlying mechanisms involved.MethodsPdx1-Cre;LSL-KrasG12D/+ mice were interbred with mitosis luciferase reporter mice, rendered diabetic with streptozotocin and treated or not with carnosinol (FL-926-16), a selective scavenger of reactive carbonyl species (RCS) and, as such, an inhibitor of AGE formation. Mice were monitored for tumour development by in vivo bioluminescence imaging. At the end of the study, pancreatic tissue was collected for histology/immunohistochemistry and molecular analyses. Mechanistic studies were performed in pancreatic ductal adenocarcinoma cell lines challenged with high glucose, glycolysis- and glycoxidation-derived RCS, their protein adducts AGEs and sera from diabetic patients.ResultsCumulative incidence of invasive PaC at 22 weeks of age was 75% in untreated diabetic vs 25% in FL-926-16-gtreated diabetic and 8.3% in non-diabetic mice. FL-926-16 treatment suppressed systemic and pancreatic carbonyl stress, extracellular signal-regulated kinases (ERK) 1/2 activation, and nuclear translocation of Yes-associated protein (YAP) in pancreas. In vitro, RCS scavenging and AGE elimination completely inhibited cell proliferation stimulated by high glucose, and YAP proved essential in mediating the effects of both glucose-derived RCS and their protein adducts AGEs. However, RCS and AGEs induced YAP activity through distinct pathways, causing reduction of Large Tumour Suppressor Kinase 1 and activation of the Epidermal Growth Factor Receptor/ERK signalling pathway, respectively.ConclusionsAn RCS scavenger and AGE inhibitor prevented the accelerating effect of diabetes on PainINs progression to invasive PaC, showing that hyperglycaemia promotes PaC mainly through increased carbonyl stress. In vitro experiments demonstrated that both circulating RCS/AGEs and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by YAP activation, hence providing a molecular mechanism underlying the link between diabetes and PaC (and cancer in general).

Highlights

  • Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism

  • In vitro experiments demonstrated that both circulating reactive carbonyl species (RCS)/advanced glycation end-products (AGEs) and tumour cell-derived carbonyl stress generated by excess glucose metabolism induce proliferation by Yes-associated protein (YAP) activation, providing a molecular mechanism underlying the link between diabetes and PaC

  • Though type 2 diabetes is the main contributor to this problem, the entity and temporal trajectory of PaC risk were recently reported to be similar in type 1 diabetes [6], suggesting a common mechanism related to hyperglycaemia

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Summary

Introduction

Type 1 and 2 diabetes confer an increased risk of pancreatic cancer (PaC) of similar magnitude, suggesting a common mechanism. Though type 2 diabetes is the main contributor to this problem, the entity and temporal trajectory of PaC risk were recently reported to be similar in type 1 diabetes [6], suggesting a common mechanism related to hyperglycaemia This concept is supported by the recent finding that PaC incidence increases linearly with increasing fasting glucose levels, even within the normal range [7]. Previous studies have shown that type 2 diabetes induced by a high-fat diet promotes PaC [8, 9] This experimental model of the metabolic syndrome does not allow assessing the role of hyperglycaemia independent of confounding factors such as obesity and hyperinsulinemia, hindering the understanding of the mechanisms underlying the risk conferred by hyperglycaemia. The resulting irreversible adducts (i.e., AGEs) accumulate in tissues, where they can exert further biological effects through interaction with specific receptors [12, 13]

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