Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

Abstract

Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.

Pancreatic cancer: A review of epidemiology, trend, and risk factors

“…When the carbonyl group of reducing sugar like glucose or its oxidation or lipid peroxidation products react with the ε-amino group of lysine or the guanidino group of arginine, AGEs can be formed, including imidazolones, pentosidine, pyrraline, and N ε -(carboxymethyl)lysine (CML)[ 118 ]. AGEs accumulate in sera and tissues during the ageing process because of glycolytic and oxidative reactions, reduced activity of the detoxification systems, cigarette smoking, and consumption of high-temperature-processed foods[ 8 ]. Excessively high concentrations of AGEs in human tissue and circulation accelerate oxidative stress and inflammation, which may play a pathogenic role[ 118 ].…”

“…Excessively high concentrations of AGEs in human tissue and circulation accelerate oxidative stress and inflammation, which may play a pathogenic role[ 118 ]. Exogenous AGEs, in particular those derived from the diet, have been claimed to contribute to several disease processes, including cancer in general and, specifically PDAC[ 8 ]. CML is frequently used as a marker for AGEs in general[ 119 ].…”

“…Clinically, pancreatic cancer is the general term for malignant tumor formed in the epithelial cells of glandular structures in the pancreatic ductal cells, referred to as adenocarcinoma[ 6 ], and pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of pancreatic cancers[ 7 ]. Due to the poor survival outcomes, PDAC is the seventh leading cause of global cancer death despite being the 10th most common cancer[ 8 ]. Other less common exocrine pancreatic cancers include adenosquamous carcinoma, squamous cell carcinoma, giant cell carcinoma, acinar cell carcinoma, and small cell carcinoma.…”

Diabetic Complications and Oxidative Stress: A 20-Year Voyage Back in Time and Back to the Future

“…Together with RCS derived from oxidative and non-oxidative metabolism of glucose and lipids [ 71 ], these RCS contribute to tissue accumulation of their final protein adducts, collectively known as advanced glycation end-products (AGEs). In particular, the α-hydroxyaldehyde formed from L-serine by neutrophilic MPO activity is able to form cross-links and generate Nε-(carboxymethyl)lysine (CML), a major AGE found in vivo that mainly derives from glyco- and lipoxidation reactions [ 72 , 73 ]. Therefore, ROS and other MPO-derived reactive compounds may promote the development and progression of diabetic complications by contributing to the accumulation of AGEs [ 74 ].…”

“…They also suggest potential avenues for prevention and treatment of end-organ damage induced by DM. From a mechanistic perspective, the glycolysis by-product MGO has now been recognized as a potential driver for both the development of diabetic complications [ 130 , 168 ] and the progression of several highly glycolytic cancers [ 73 ]. In addition, a metabolic rewiring similar to that of glycolytic tumor cells has recently been described as a feature of diabetic complications [ 144 , 149 ].…”