We compared circulating levels of: a) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), b) follistatins-activins (follistatin-like [FSTL]3, activin B), c) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy associated plasma protein [PAPP]-A) in two studies: a) 18 individuals with early stage NAFLD vs. 14 controls (study 1; early NAFLD study) and in b) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs. 50 controls (24 lean and 26 obese) (study 2).
The results showed that paeoniflorin significantly decreased serum insulin and glucagon levels, improved insulin sensitivity and serum lipids profiles, and alleviated hepatic steatosis in fructose-fed rats.
Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis.
GLP-1 analogues pleiotropic effects proved to be efficacious in T2DM subjects not only reducing liver steatosis and ameliorating NAFLD and NASH, but also in lowering plasma glucose and liver inflammation, improving cardiac function and protecting from kidney dysfunction.
Clinical and pre-clinical studies, discussed in this review, suggest that modulation of GLP1/miRNAs pathway may be a useful and innovative therapeutic strategy for prevention and treatment of metabolic disorders, such as diabetes mellitus and liver steatosis.
GLP-1 RAs also showed favorable results on reductions in transaminases and steatosis and improvements in insulin sensitivity and weight loss but lack efficacy data for resolution of NASH or improvement in fibrosis scores.
The results may suggest that surgery-induced hypothyroidism increases GLP-1, the actions of which may in part be responsible for the reduction in water intake, appetite and hepatic steatosis.
In addition, an increase in the regions of steatohepatitis, hepatocyte hypertrophy, and lipid droplet deposit-related renal tubular vacuolation degenerative lesions were detected, with noticeable expansion and hyperplasia of the pancreatic islets, and an increase in glucagon- and insulin-producing cells, insulin/glucagon cell ratios in the endocrine pancreas and hepatic lipid peroxidation, as well as decreased zymogen contents.
Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis.