NAFLD as a continuum: from obesity to metabolic syndrome and diabetes

Abstract

Background: The prevalence of non-alcoholic fatty liver disease (NAFLD) has been increasing rapidly. It is nowadays recognized as the most frequent liver disease, affecting a quarter of global population and regularly coexisting with metabolic disorders such as type 2 diabetes, hypertension, obesity, and cardiovascular disease. In a more simplistic view, NAFLD could be defined as an increase in liver fat content, in the absence of secondary cause of steatosis. In fact, the clinical onset of the disease is a much more complex process, closely related to insulin resistance, limited expandability and dysfunctionality of adipose tissue. A fatty liver is a main driver for a new recognized liver-pancreatic α-cell axis and increased glucagon, contributing to diabetes pathophysiology.

Main text: This review will focus on the clinical and pathophysiological connections between NAFLD, insulin resistance and type 2 diabetes. We reviewed non-invasive methods and several scoring systems for estimative of steatosis and fibrosis, proposing a multistep process for NAFLD evaluation. We will also discuss treatment options with a more comprehensive view, focusing on the current available therapies for obesity and/or type 2 diabetes that impact each stage of NAFLD.

Conclusion: The proper understanding of NAFLD spectrum-as a continuum from obesity to metabolic syndrome and diabetes-may contribute to the early identification and for establishment of targeted treatment.

Keywords: Diabetes; Fatty liver; Metabolic syndrome; NAFLD; NASH; Obesity.

Fig. 1

Pathophysiology of NAFLD as a continuum from obesity to metabolic syndrome and diabetes. Environmental factors affect the expression of genes, inducing weight gain. When the capacity of expansion of subcutaneous adipose tissue (AT) is reached, an increased free fatty acids (FFAs) mobilization arises, resulting in visceral and ectopic fat deposition. One ectopic site is the muscle, where increased FFAs deposition promotes insulin resistance (IR), inhibiting insulin-mediated glucose uptake. On the other hand, AT insulin resistance facilitates lipolysis and increases the flux of FFAs to the liver, inducing hepatic IR and enhancing glucose production, de novo hepatic lipogenesis, VLDL release and atherogenic dyslipidemia. FFAs spill over into the pancreas, causing β-cell dysfunction by lipotoxicity, hyperglycemia and diabetes (the twin cycle hypothesis). Increased liver fat also promotes hepatic glucagon resistance (GR) over the amino acids (AAs) metabolism, reducing ureagenesis and resulting in hyper-aminoacidemia. Increased AAs stimulate glucagon production to compensate for hepatic GR, and a vicious cycle is installed (the liver-pancreas axis). This hyperglucagonemia also leads to an increased hepatic glucose release. The globally IR state results in hyperinsulinemia, which may enhance sodium reabsorption and increase sympathetic nervous system activity, contributing to the hypertension. Inflamed dysfunctional AT becomes more insulin resistant and releases pro-inflammatory adipokines, while decreases anti-inflammatory adiponectin. In the liver, triglycerides and toxic metabolites induce lipotoxicity, mitochondrial dysfunction and endoplasmic reticulum stress, leading to hepatocyte damage, apoptosis and fibrosis. These dysfunctional hepatocytes synthesize and secret the dipeptidyl peptidase 4 (DPP4), which promotes inflammation of AT macrophages and more IR. AAs amino acids, AT adipose tissue, DPP4 dipeptidyl peptidase 4, FFA free fatty acid, GR glucagon resistance, HDL high-density lipoprotein, IR insulin resistance, LDL low-density lipoprotein, NAFLD nonalcoholic fatty liver disease, SAT subcutaneous adipose tissue, SNS sympathetic nervous system, VAT visceral adipose tissue, VLDL very low-density lipoprotein. Pointed arrows indicate stimulation or enhancement, while blunt ends indicate inhibition or repression. Dashed arrows indicate progressive reduction in a pathway