Metabolic liver disease in diabetes - From mechanisms to clinical trials

Abstract

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.

Keywords: Biomarkers; Clinical trials; Fatty liver; Glucose-lowering drugs; Insulin resistance; Type 2 diabetes.

Fig. 1

Communication between hepatic and extrahepatic tissues during development of NAFLD 1) hypercaloric energy-dense diets could induce intestinal dysbiosis and promote fat storage in adipose tissues resulting in visceral adiposity. Other intestinal changes include intestinal permeability, which facilitates translocation of inflammatory LPS into the liver. Also, suppression of FIAF by gut dysbiosis promote fat storage in peripheral tissues 2) excess TAG in adipose tissue stimulate inflammation and insulin resistance. There is no consensus about if inflammation precedes insulin resistance or vice versa. Insulin resistance leads to increased lipolysis and release of FFA, which promote ectopic fat deposition in liver and muscle. Adipose tissue-derived cytokines and adipokines could also regulate insulin sensitivity in liver and muscle 3) increased fat storage in the skeletal muscle could be associated with increased insulin resistance leading to suppression of insulin-stimulated GLUT4-glucose uptake by myocytes and decrease of glycogenesis [25] 4) similarly, liver steatosis could be associated with hepatic insulin resistance i.e., increased gluconeogenesis and decreased glycogen synthesis. Importantly, metabolites of β-oxidation of FFA could allosterically activate gluconeogenesis-related enzymes [25] 5) hyperglycemia arise as a result of muscle and liver insulin resistance 6) pancreas secretes more insulin in response to peripheral and hepatic insulin resistance leading to hyperinsulinemia 7) genetic variants such as PNPLA3 and TM6SF2 interfere with lipid metabolism and export promoting liver steatosis. EGP, endogenous glucose production; FFA, free fatty acids; FIAF, fasting-induced adipocyte factor; GNG, gluconeogenesis; IL, interleukin; INF, inflammation; INS-R, insulin resistance; LPS, lipopolysaccharide; TNF, tumor necrosis factor.

Fig. 2

Altered signaling and pathogenic mechanisms in hepatocytes during NAFLD progression a) insulin signaling in healthy hepatocytes suppress endogenous glucose production through inhibition of gluconeogenesis and increasing glycogen synthesis b) steatotic hepatocytes are characterized by disturbed lipid metabolism i.e., 1) there is increase in FFA influx which enters the liver through fatty acid transport proteins (FATP) and leads to 2) increased mitochondrial fatty acid oxidation, 3) formation of lipid toxic intermediates e.g. sn 1,2 DAG which stimulates PKCε to phosphorylate Thr1160 in insulin receptor leading to hepatic insulin resistance i.e., increased gluconeogenesis and decreased glycogen synthesis. Again, FFA metabolites e.g. acetyl CoA could directly stimulate gluconeogenesis [25] 4) increased glucose enters the liver mainly through glucose transporter (GLUT2) and activates ChREBP pathway. Insulin-signaling activates SREBP1C pathway too. Both pathways increase DNL c) after progression to NASH, mitochondrial flexibility is lost leading to decreased fatty acid oxidation. Together with other toxic intermediate lipid, ER stress and ROS generation increase leading to hepatocytes death and release of inflammatory cytokines and chemokines. AKT, protein kinase B; ChREBP, carbohydrate response element-binding protein; DAG, sn 1,2 diacylglycerol; DNL, de novo lipogenesis; EGP, endogenous glucose production; ER, endoplasmic reticulum; FAO, fatty acid oxidation; FFA, free fatty acids; GLU, glucose; GNG, gluconeogenesis; INS, insulin; INS-R, insulin resistance; IR, insulin receptor; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; ROS, reactive oxygen species; SREBP1C; sterol regulatory element-binding proteins; TAG, triacylglycerol.

Fig. 3

Multicellular cross-talks during NAFLD progression 1) insulin resistance is a potential nexus between T2DM and NAFLD that leads to glucolipotoxicity, which stimulates ROS generation and increases endoplasmic reticulum stress resulting in cell death e.g., apoptosis and necroptosis 2) dead cells activate HSC and Kupffer cells by various mechanisms including apoptotic bodies engulfment and DAMP release 3) “find me” signals released by dead cells stimulate inflammatory cells infiltration to the liver 4) lipid stressed HC could secrete EV that stimulate fibrogenic gene expression in HSC 5) free cholesterol and FFA could also directly activate HSC 6) intestine-derived LPS activate both HSC and KC 7) microbiota-derived ethanol precipitates in increased ROS generation 8) activated KC secrete TGF-β resulting in activation of HSC 9) defenestrated LSEC (LSEC capillarization) support HSC activation and acquire inflammatory phenotype that induces liver inflammation. As a result of HSC activation, ECM production increases, leading to liver fibrosis, which could progress further to cirrhosis or liver cancer [179]. DAMP, damage-associated molecular patterns; ECM, extracellular matrix; ER, endoplasmic reticulum; EV, extracellular vesicle; FFA, free fatty acids; HC, hepatocyte; HSC, hepatic stellate cells; KC, Kupffer cells; LPS, lipopolysaccharide; LSEC, liver sinusoidal endothelial cells; MC, monocytes; ROS, reactive oxygen species; TGF, tumor growth factor.