The Role of Type 2 Diabetes in Pancreatic Cancer

Abstract

The incidence of type 2 diabetes mellitus (T2DM) and its potential complications, such as cancers, are increasing worldwide at an astounding rate. There are many factors such as obesity, diabetes, alcohol consumption, and the adoption of sedentary lifestyles that are driving pancreatic cancer (PC) to become one of the leading causes of cancer mortality in the United States. PC is notorious for its generic symptoms and late-stage presentation with rapid metastasis. The connection between T2DM and the risk of PC development is multifaceted and complex. Some of the proposed theories reveal that chronic inflammation, insulin resistance, hyperinsulinemia, hyperglycemia, and abnormalities in the insulin and insulin-like growth factor axis (IGF) contribute to the disease association between these two conditions. This literature review aims to highlight relevant studies and explore the molecular mechanisms involved in the etiology of diabetes and its impact on PC development, as well as the role of anti-diabetic agents on PC. Despite extensive studies, the exact interaction between T2DM and PC remains obscure and will need further investigation. According to current knowledge, there is a substantial link between diabetes, obesity, and dietary patterns in the development and progression of PC. Consequently, focusing our efforts on preventive measures by reducing modifiable risk factors remains the most effective strategy to reduce the risk of PC at this time. Antidiabetic drugs can have various effects on the occurrence and prognosis of PC with metformin offering a clear benefit of inhibiting PC and insulin increasing the risk of PC. The development of future novel therapies will require a deeper knowledge of the triggering mechanisms and interplay between these two disease states.

Keywords: antidiabetic agents; diabetes mellitus type 2; pancreatic ductal adenocarcinoma; pancreatic neoplasm; type 2 diabetes.

Figure 1. A schematic representation of some of the common risk factors for pancreatic cancer.

Image created using Google Slides [13]. MAPK: mitogen-activated protein kinase; IGF-1: insulin-like growth factor 1; IL-6: interleukin-6; TNF-α: tumor necrosis factor-alpha; VEGF: vascular endothelial growth factor; NF-κB: nuclear factor kappa B; IL-1β: interleukin-1 beta; TAN: tumor-associated neutrophil; PSC: pancreatic stellate cells; ADH1: alcohol dehydrogenase 1; ALDH2: alcohol dehydrogenase 2; ROS: reactive oxygen species, K-RAS: Kirsten rat sarcoma virus gene; BRCA2: breast cancer gene 2

Figure 2. Mechanisms involved between type 2 diabetes mellitus and pancreatic cancer.

Created using Google Slides by Sara Waqar [28]. AGEs: advanced glycation end products; AMPK: adenosine monophosphate protein-activated kinase; IGF-1: insulin-like growth factor-1; LKB: liver kinase B; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin; NF-κB: nuclear factor kappa B; PI3K: phosphatidyl inositol-3 kinase; STAT3: signal transducer and activator of transcription 3; TGF-β1: transforming growth factor-β1; TME: tumor microenvironment; PDX1: pancreatic and duodenal homeobox-1; HNF1A: hepatocyte nuclear factor-1 alpha; UCP2: uncoupling protein 2