Nevertheless, prior animal and human studies on incretin mimetics, glucagon like peptide-1 receptor agonists (GLP-1 RA) approved for T2DM treatment, have provided indirect evidence that they may also ameliorate NAFLD/NASH, whereas dipeptidyl dipeptidase-4 inhibitors (DDP-4i) were not better than placebo in reducing liver fat in T2DM patients with NAFLD.
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).
A glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide (LR) had been experimentally and clinically shown to ameliorate nonalcoholic fatty liver disease (NAFLD).
Until then pioglitazone, GLP-1 RA, SGLT2i, and statins plus ezetimibe, especially in combination might be useful for treating the huge number of patients with NAFLD/NASH.
Lipid-induced impairment of hepatic sensitivity, not only to insulin but potentially also to glucagon, resulting in both hyperinsulinemia and hyperglucagonemia, may therefore contribute to the development of T2D at least in a subset of individuals with NAFLD.
More recently, there is an increasing interest regarding the effects of newer anti-diabetic drugs, such as dipeptidyl peptidase 4 inhibitors (DPP-4i), sodium glucose cotransporter 2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on NAFLD/NASH.
This study suggests that lower glucagon relative insulin may be independently associated with nonalcoholic fatty liver disease in participants with type 2 diabetes.
Due to their overall safety and efficacy, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming one of the cornerstones for the management of both obesity and T2DM, and a novel alternative for the treatment of NAFLD.
Some new pharmacological strategies act broadly to alter energy balance or influence pathways that contribute to NAFLD (e.g., agonists for PPAR γ, PPAR α/δ, FXR and analogs for FGF-21, and GLP-1).
The effects of gut-derived hormone-associated drugs, such as glucagon-like peptide-1 analog and recombinant variant of fibroblast growth factor 19, and other new treatment strategies for NAFLD/NASH have also been reported.
The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.
Fasting levels of amino acids and glucagon in plasma were measured, using validated ELISAs and high-performance liquid chromatography, in obese, middle-aged individuals with I) normal glucose tolerance (NGT) and NAFLD, II) T2D and NAFLD, III) T2D without liver disease, and IV) NGT and no liver disease.
The new anti-diabetic medication classes, the sodium-glucose co-transporter-2 inhibitors (SGLT2i) and the glucagon like peptide receptor agonists (GLP1 RA) for patients with NAFLD/NASH, CKD and T2DM are useful because they ameliorate NAFLD/NASH, delay the evolution of CKD, and substantially reduce CVD and all-cause mortality.
In the current study, we showed that the serum GLP-1 levels of NAFLD patients were similar to those of normal controls, but hepatic GLP-1R expression was significantly downregulated in NAFLD patients.
From this analysis, we can conclude that the multi-target beneficial action of the GLP-1 analogues could explain the positive effects observed in animal and human models on progression of NAFLD to NASH.
Women with NAFLD had a higher BMI (P = 0.0002) and waist circumference (P = 0.0003), increased insulin resistance (P = 0.0004), and delayed suppression of glucagon after the OGTT (P < 0.0001), but NAFLD was not associated with the degree of glucose intolerance (P = 0.2196).
The mean values of fasting and postprandial plasma glucagon levels were higher in T2DM patients with NAFLD (<i>n</i> = 37) as compared to T2DM patients without NAFLD (<i>n</i> = 44).
To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)).
The opportunity to take into account NAFLD in T2MD prevention and care has stimulated several clinical studies in which antidiabetic drugs, such as metformin, thiazolidinediones, GLP-1 analogues and DPP-4 inhibitors have been evaluated in NAFLD patients.