Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth

Abstract

Background Diabetes mellitus type 2 (DM2) is a modifiable risk factor associated with pancreatic carcinogenesis and tumor progression on the basis of epidemiology studies, but the biological mechanisms are not completely understood. The purpose of this study is to demonstrate direct evidence for the mechanisms mediating these epidemiologic phenomena. Our hypothesis is that DM2 accelerates pancreatic cancer growth and that metformin treatment has a beneficial impact. Methods To determine the effect of glucose and insulin in pancreatic cancer proliferation, we used conditioned media to mimic DM2 conditions. Also, we studied the effect of anti-diabetic drugs, particularly metformin and rosiglitazone on pancreatic cancer growth. We established orthotopic/syngeneic (Leprdb/db) mouse cancer models to evaluate the effect of diabetes on pancreatic tumor growth and aggressiveness. Results Our results showed that diabetes promotes pancreatic tumor growth. Furthermore, enhanced tumor growth and aggressiveness (e.g. epithelial–mesenchymal transition) can be explained by functional transcriptomic and metabolomic changes in the mice with diabetes, namely via activation of the AKT/mTOR pathway. Metformin treatment suppressed the diabetes-induced AKT/mTOR pathway activation and tumor growth. The metabolic profile determined by mass spectrum showed important changes of metabolites in the pancreatic cancer derived from diabetic mice treated with metformin. Conclusions Diabetes mellitus type 2 has critical effects that promote pancreatic cancer progression via transcriptomic and metabolomic changes. Our animal models provide strong evidence for the causal relationship between diabetes and accelerated pancreatic cancers. This study sheds a new insight into the effects of metformin and its potential as part of therapeutic interventions for pancreatic cancer in diabetic patients.

Diabetes and pancreatic cancer: Exploring the two-way traffic

“…Experimental evidence is emerging to explain the molecular mechanism linking T2DM and PDAC. They include the roles of cellular senescence promoted by both T2DM and obesity[ 43 ], advanced glycation end products and its receptor[ 44 ], metabolic reprogramming by hyperglycaemia[ 45 ] and the interplay between non-alcoholic fatty pancreas development in the milieu of obesity and diabetes[ 46 ].…”

Harness the functions of gut microbiome in tumorigenesis for cancer treatment

“…Thus, imidazole propionate level is high in T2D patients [ 84 , 85 ]. Insulin resistance leads to a potential to promote cancer growth: impacts include causing hyperinsulinema, hyperglycemia, and mTOR activation [ 86 , 87 ]. Indeed, imidazole propionate can activate mTOR [ 83 ].…”

“…Indeed, imidazole propionate can activate mTOR [ 83 ]. Insulin resistance results in metabolic alterations, which are important in supporting the uncontrolled growth of tumor cells [ 86 , 88 , 89 ]. Therefore, it is conceivable that impacts of gut microbiota dysbiosis on causing insulin resistance might be involved in promoting cancer growth.…”

“…Prevotella subsequently protects against Bacteroides ‐induced glucose intolerance [ 212 ]. Glucose intolerance can lead to accelerated tumor growth [ 86 , 213 ]. A recent study indicates that ARAF mutations conferred resistance to RAF inhibitor [ 214 ].…”

Application of Mass Spectrometry in Pancreatic Cancer Translational Research

“…Unfortunately, the specific mechanism of the interaction between diabetes and PC is not fully understood, which is not conducive to the development of strategies for early detection of PC in people with diabetes. Velazquez et al expect to use transcriptome and metabolome changes to reveal the mechanism of diabetes that promotes PC growth and invasion (34). They found that type 2 diabetes mellitus accelerates cancer growth by driving metabolic reprogramming (mainly kynurenine, tryptophan, taurine, and choline pathways), whereas metformin therapy reverses metabolic reprogramming to inhibit cancer growth.…”