Abstract
Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.
Highlights
Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia due to inadequate insulin secretion and/or insulin resistance [1]
Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) patients are prone to cancer development, more evidence is available for T2DM, so the current review is focused on this specific population
Recent data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study showed an inverse association between plasma levels of several methylglyoxal and glyoxal-derived advanced glycation endproducts (AGEs) species and Colorectal cancer (CRC) risk [151]. These findings indicate that measurement of circulating AGEs is likely insufficient to monitor CRC risk and activity since it does not reflect AGEs accumulation in situ [151]
Summary
Diabetes mellitus (DM) is a complex metabolic disorder characterized by chronic hyperglycemia due to inadequate insulin secretion and/or insulin resistance [1]. It has been demonstrated that insulin stimulates proliferation of Caco-2 and HT-29 cell lines [30] and enhances cholesterol uptake and lipid accumulation in Caco-2 cells through elevation of cholesterol transporter scavenger receptor, class B, type I (SR-BI) mRNA, and protein levels [31] This latter effect of insulin might be of special interest, noting the increasing demand of malignant cells for cholesterol and evidence of disturbed lipid homeostasis in CRC [32,33]. IR can contribute to the enhanced effects of IGFs since hyperinsulinemia suppresses levels of IGF binding proteins (IGFBPs), increasing the bioavailability of IGFs [51] Such inhibitory effects of insulin on IGFBPs should not be observed as straightforward, since novel data indicate that IGFBPs themselves exhibit direct cellular effects, independently of IGFs, so far conducted studies yielded mainly inconclusive results regarding the role of IGFBPs in CRC [42,52,53,54]. Having in mind incompletely understood mechanisms of resistin actions during both IR and CRC development, future studies are warranted in this area
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