Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review

Abstract

Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.

Statin Induced Changes in Rat Pancreatic Tissue: A Histological and Biochemical Perspective

“…This may impair acinar enzyme production and islet hormone secretion, providing a histopathological basis for clinical reports of statininduced pancreatitis and diabetes. 10 Notably, the patterns observed here evoke the initial changes in type 1 diabetes pathogenesis. Lymphocytic infiltration and lipomatosis mark the early stages, followed by progressive islet destruction.…”

Prognostic significance of glucose‐lipid metabolic index in pancreatic cancer patients with diabetes mellitus

“…These effects are primarily exerted through regulating the structure and function of cell membranes, cellular homeostasis, and hormone synthesis. 47 , 48 , 49 Therefore, with reference to the optimization of TyG‐neck circumference (TyG‐NC), TyG‐neck circumference to height ratio (TyG‐NHtR), TyG‐waist circumference (TyG‐WC), TyG‐waist to height ratio (TyG‐WHtR), TyG‐body mass index (TyG‐BMI), 22 we optimized TyG‐BMI, and the product of TyG‐BMI and TC/HDL‐c was used as the GLMI. The level of IR in PC patients with diabetes was evaluated using GLMI.…”

Global Burden of Pancreatic Cancer Attributable to High Body-Mass Index in 204 Countries and Territories, 1990–2019

“…Although etiopathogenetic mechanisms that would explain the link between a high BMI and pancreatic cancer were not fully understood, some authors suggested that pancreatic fatty infiltration, chronic inflammation, altered cellular metabolism, hormone dysregulation, microbial dysbiosis, or immune cell infiltration may be involved in pancreatic carcinogenesis [29,30]. It is known that obesity favors the release of pro-inflammatory cytokines such as tumor necrosis factor α and Interleukin-6, which are linked to the development of inflammation, and the onset of cancer [31]. Also, one study found that fatty acid-binding protein 4 (that induces inflammation to promote cancer cell migration, invasion, and metastasis under obese conditions) was overexpressed in the serum of patients with obesity and was associated with poor overall survival in pancreatic cancer [32].…”