Reenvisioning Traditional to Regenerative Therapeutic Advances in Managing Nonalcoholic Fatty Liver Disease in Diabetes Mellitus

Abstract

Reports indicate the increasing prevalence of liver disorders in diabetes mellitus (DM) patients. Clinically, it has also been revealed that the existence of nonalcoholic fatty liver disease (NAFLD) enhances the incidence of type 2 diabetes mellitus (T2DM), while T2DM exacerbates NAFLD to extremely severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. This implies the coexistence and bidirectional nature of NAFLD and T2DM, which function synergistically to drive adverse consequences in clinical practice. For treatment of such comorbid state, though the existing practices such as lifestyle management, traditional Chinese medicines (TCM), and pharmaceuticals have offered somewhat relief, the debate continues about the optimal therapeutic impacts. Recent developments in the field of tissue engineering have led to a renewed interest in novel biomaterial alternatives such as stem cells. This might be attributable to their differentiation potential towards hepatic and pancreatic lineage. These cellular therapies could be further complemented by platelet-derived biomaterials, TCM formulations, or any specific drug. Based on these abovementioned approaches, we aimed to comprehensively analyze various preclinical and clinical studies from traditional to regenerative therapeutic approaches in managing concomitant NAFLD and T2DM.

Figure 1

Association between the pathophysiological duo of NAFLD and DM and its treatment. (a) The mechanistic insight underlying NAFLD and DM. NAFLD participates in the development of T2DM by enhancing glucose production and insulin resistance in the liver. T2DM and systemic insulin resistance induces the initiation and progression of NAFLD by increasing levels of FFA and TG from peripheral tissues to the liver. If remain untreated, NAFLD further progresses from NASH, cirrhosis, to hepatocellular carcinoma. (b) Journey of therapeutic alternatives from traditional to regenerative medicines, including lifestyle management, TCM, pharmaceuticals, stem cells, and PRP. NAFLD: nonalcoholic fatty liver disease; FFA: free fatty acid; TG: triglycerides; NASH: nonalcoholic steatohepatitis; T2DM: type 2 diabetes mellitus; TCM: traditional Chinese medicines; PRP: platelet-rich plasma.

Figure 2

Stem cell-based regenerative therapies for NAFLD in T2DM. (a) BMSC, ADSC, and UCMSC-based regenerative therapies. NAFLD: nonalcoholic fatty liver disease; T2DM: type 2 diabetes mellitus; BMSCs: bone-marrow stem cells; ADSCs: adipose-derived stem cells; UCMSCs: umbilical cord-derived stem cells; HO-1: heme oxygenase-1; IR: insulin resistance; TGF: transforming growth factor; IL: interleukin; HGF: hepatocyte growth factor; VEGF: vascular endothelial growth factor; EGF: epidermal growth factor; MMP-2: matrix metalloproteinase-2.

Figure 3

Highlights of novel therapeutic approaches by combining stem cells with the various therapeutic agent (yellow boxes) such as Ginkgo biloba extract (TCM), antioxidants (melatonin, reduced glutathione, and resveratrol), bioactive lysophospholipids (lysophosphatidic acid and sphingosine-1-phosphate), and glucagon-like peptide-1 receptor agonist (liraglutide) and their impacts (blue boxes). Up and down arrows indicate the increased and decreased levels, respectively. MDA: malondialdehyde; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; SOD: superoxide dismutase; GSH-Px: glutathione peroxidase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; TBIL: total bilirubin; GOT: glutamic-oxaloacetic transaminase; GPT: glutamic-pyruvic transaminase; NF-κB: nuclear factor kappa beta; IL-10: interleukin-10; ERK: extracellular signal-regulated kinases; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; FBG: fasting blood glucose; HbA1c: hemoglobin A1C; HOMA-IR: homeostatic model assessment of insulin resistance; TLR4: Toll-like receptor 4; 8-OHdG: 8-hydroxydeoxyguanosine (oxidative stress marker).

Figure 4

Association between a pathophysiological duo of NAFLD and DM and its treatment. (a) The mechanistic insight underlying NAFLD and DM. NAFLD participates in the development of T2DM by enhancing glucose production and insulin resistance in the liver. T2DM and systemic insulin resistance induce the initiation and progression of NAFLD by increasing levels of FFA and TG from peripheral tissues to the liver. If remain untreated, NAFLD further progresses from NASH, cirrhosis, to hepatocellular carcinoma. (b) Journey of therapeutic alternatives from traditional to regenerative medicines, including lifestyle management, TCM, pharmaceuticals, stem cells, and PRP. NAFLD: nonalcoholic fatty liver disease; FFA: free fatty acid; TG: triglycerides; NASH: nonalcoholic steatohepatitis; T2DM: type 2 diabetes mellitus; TCM: traditional Chinese medicines; PRP: platelet-rich plasma.