Leptin as a Key Player in Insulin Resistance of Liver Cirrhosis? A Cross-Sectional Study in Liver Transplant Candidates

Abstract

Insulin resistance is associated with increased risk of death and liver transplantation in the cirrhotic population, independent of disease aetiology. However, factors accounting for insulin resistance in the context of cirrhosis are incompletely understood. This study aimed to investigate the association between adiponectin and leptin with insulin resistance in cirrhotic patients and to assess the influence of disease severity on insulin resistance and metabolic status. This cross-sectional study included 126 non-diabetic cirrhotic transplant candidates. The homeostasis model assessment 2 model was used to determine the insulin resistance index, and fasting adiponectin, leptin, insulin, c-peptide, glucose, HbA1c, and lipid profiles were analysed. Insulin resistance was detected in 83% of subjects and associated with increased leptin, fasting plasma glucose and body mass index, and lower triglyceride levels. Logistic regression analysis identified leptin and triglycerides as independent predictors of insulin resistance (OR 1.247, 95% CI 1.076–1.447, p = 0.003; OR 0.357, 95% CI 0.137–0.917, p = 0.032.). Leptin levels remained unchanged, whereas adiponectin levels increased (p < 0.001) with disease progression, and inversely correlated with HbA1c (ρ = −0.349, p < 0.001). Our results indicate that leptin resistance, as indicated by elevated leptin levels, can be regarded as a contributing factor to insulin resistance in cirrhotic patients, whereas triglycerides elicited a weak protective effect. Progressively increasing adiponectin levels elicited a positive effect on glucose homeostasis, but not insulin sensitivity across disease stages.

Molecular Mechanism Contributing to Malnutrition and Sarcopenia in Patients with Liver Cirrhosis

“…Hepatogenous insulin resistance is characterized mainly by peripheral insulin resistance in the skeletal muscle and fat tissue, while uptake of glucose in the liver is normal or even enhanced [ 98 ]. The mechanisms accounting for insulin resistance in liver cirrhosis are still largely unknown [ 99 ]. Contributing factors may include altered glycolytic enzyme activity, changes in specific glucose transporter expression or impairment of membrane receptors for insulin [ 100 ] as well as decreased first past uptake of insulin in the liver due to liver damage and shunting of blood into the systemic circulation.…”

“…Hepatogenous insulin resistance is characterized mainly by peripheral insulin resistance in the skeletal muscle and fat tissue, while uptake of glucose in the liver is normal or even enhanced [98]. The mechanisms accounting for insulin resistance in liver cirrhosis are still largely unknown [99].…”

Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases

“…In the context of chronic alcoholism, leptin has been proposed as a marker of alcohol-dependent-related liver damage, contrasting it with alcoholic-dependent patients’ disease without severe liver damage [ 224 ]. Noteworthy, leptin has been proved to be a key player in IR of liver cirrhosis independently of the disease etiology (alcohol consumption or virus infection), and IR is associated with a worse prognosis [ 225 ]. Regrettably, most of the studies conducted in humans are merely descriptive, so further mechanistic data and basic research will be needed to decipher the actual role of leptin in ALD.…”

FGF21 ameliorates hepatic fibrosis by multiple mechanisms

“…Among the activating agents, transforming growth factor-β (TGF-β) and plateletderived growth factor (PDGF) play the critical role in the regulation of activation of HSCs and the progression of brosis [17]. Besides, Leptin, a 16-kDa protein hormone, plays a key role in the development of liver brosis, which also regulated HSC activation and ECM synthesis [18,19]. Damaged hepatocytes release in ammatory, brogenic cytokines and reactive oxygen species (ROS), which could also induce the activation of HSCs [16,20].…”