Overweight and obesity are associated with increased risk of developing metabolic disorders such as diabetes and cardiovascular diseases. However, besides these metabolic diseases, excess body weight is also associated with different cancers, including gastrointestinal cancers, such as liver, pancreatic and colon cancers. Inflammation is a common feature of both obesity and cancer; however, the origin of this inflammation has been largely debated. Over the past decade, growing evidence has shown that the composition of the gut microbiota and its activity might be associated not only with the onset of inflammation but also with metabolic disorders and cancer. Here, we review the links between the gut microbiota, gut barrier function and the onset of low-grade inflammation in the development of gastrointestinal cancer. We also describe the mechanisms by which specific microorganism-associated molecular patterns crosstalk with the immune system and how the metabolic activity of bacteria induces specific signalling pathways beyond the gut that eventually trigger carcinogenesis.

Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer.

Role of cAMP and phosphodiesterase signaling in liver health and disease.

Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM) Both multisystem diseases share several common mechanisms Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM

Metabolic liver disease in diabetes - From mechanisms to clinical trials.

Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies

The GLP-1R agonist liraglutide limits hepatic lipotoxicity and inflammatory response in mice fed a methionine-choline deficient diet.

Epidemiological studies have demonstrated a close association of type 2 diabetes and hepatocellular carcinoma (HCC). Exenatide (Ex-4), a potent diabetes drug targeting glucagon-like peptide-1 receptor (GLP-1R), is protective against non-alcoholic fatty liver disease (NAFLD). However, the Ex-4 function and GLP-1R status have yet been explored in HCC. Herein we investigated the effect of Ex-4 in diethylnitrosamine (DEN)-treated mice consuming control or high-fat high-carbohydrate diet. Administration of Ex-4 significantly improved obesity-induced hyperglycemia and hyperlipidemia and reduced HCC multiplicity in obese DEN-treated mice, in which suppressed proliferation and induced apoptosis were confined to tumor cells. The tumor suppression effects of Ex-4 were associated with high expression of GLP-1R and activation of cyclic AMP (cAMP) and protein kinase A (PKA). Importantly, Ex-4 also downregulated epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 3 (STAT3), which lie downstream of cAMP-PKA signaling, resulting in suppression of multiple STAT3-targeted genes including c-Myc, cyclin D1, survivin, Bcl-2 and Bcl-xl. The growth inhibitory effects of Ex-4 were consistent in GLP-1R-abundant hepatoma cell lines and xenograft mouse model, wherein both PKA and EGFR had obligatory roles in mediating Ex-4 functions. In addition, Ex-4 also effectively suppressed inflammatory and fibrotic phenotypes in mice fed with methionine-choline-deficient (MCD) diet and choline-deficient ethionine-supplemented (CDE) diet, respectively. In summary, Ex-4 elicits protective functions against NAFLD and obesity-associated HCC through cAMP-PKA-EGFR-STAT3 signaling, suggesting its administration as a novel approach to reduce HCC risk in diabetic patients.

M Zhou

Papers

The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP–PKA–EGFR–STAT3 axis