NAFLD and Diabetes: Two Sides of the Same Coin? Rationale for Gene-Based Personalized NAFLD Treatment

Abstract

The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly and at the forefront of worldwide concern. Characterized by excessive fat accumulation in the liver, NAFLD regularly coexists with metabolic disorders, including type 2 diabetes, obesity, and cardiovascular disease. It has been well established that the presence of NAFLD increases the incidence of type 2 diabetes, while diabetes aggravates NAFLD to more severe forms of steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, recent progress on the genotype/phenotype relationships in NAFLD patients indicates the development of NAFLD with a relative conservation of glucose metabolism in individuals with specific gene variants, such as the patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 protein (TM6SF2) variants. This review will focus on the clinical and pathophysiological connections between NAFLD and type 2 diabetes and will also discuss a disproportionate progression of NAFLD and diabetes, and the different responses to lifestyle and drug intervention in NAFLD patients with specific gene variants that may give insight into personalized treatment for NAFLD.

Fat and Sugar—A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease

“…Nevertheless, no association between the incidence of NAFLD and glycemic control or degenerative diabetic complications was confirmed, indicating that NAFLD in diabetic patients may develop and progress independently of diabetes progression itself [57]. In contrast, patients with T2D complicated by NAFLD remain at an increased risk of NASH, advanced fibrosis, cirrhosis and hepatocellular carcinoma in the background of T2D [58][59][60]. Moreover, either improvement or transient remission of NAFLD were positively associated with reduced T2D incidence and may lead to improvement of glucose tolerance [61,62].…”

“…When periods of overnutrition are sustained, abnormal production of adipocytokines (e.g., leptin, adiponectin, and TNF-α) or hepatokines with diabetogenic properties (e.g., fetuins, RBP4, and selenoprotein P) intensify peripheral insulin resistance. In turn, insulin resistance governs peripheral lipolysis by increasing the hepatic influx of FAs and initiation of NAFLD [58]. The biological mechanisms underlying the liver response upon exposure to elevated concentrations of FAs require further study.…”

“…The presence of NAFLD increases the onset of T2D. Meanwhile, T2D is potent in accelerating the progression of NAFLD to more severe forms, including cirrhosis or hepatocellular carcinoma [58]. Therefore, screening for novel biomarkers and careful treatment recommendations for patients with T2D are justified and need to be actively pursued in the clinic.…”

Virtual metabolic human dynamic model for pathological analysis and therapy design for diabetes

“…Metabolism plays a critical role in human health and diseases (12). Perturbation of genetics and changes in lifestyle habitats, including excess sugar, excess fat and inactivity, result in the development and progression of complex metabolic diseases, such as hyperglycemia, hyperlipidemia, obesity, non-alcoholic fatty liver disease (NAFLD) (13,14) and diabetes (13,(15)(16)(17). A systems approach is necessary to elucidate the molecular mechanisms causing such metabolic dysfunctions and to propose the strategies for the prevention and treatment of them (18).…”

Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma

“…Obesity is considered a risk factor for hepatic complications such as NAFLD and HCC [5][6][7][8][9] . Although 17%-33% of the general population is estimated to be affected by NAFLD, it reaches 75% in obese individuals and is even higher in patients with type II diabetes mellitus (T2DM) [10,11] . Moreover, T2DM itself is associated with an increased risk of liver damage [12] , including HCC [13][14][15] .…”