NAFLD is primary characterized by the accumulation of intrahepatic tryglycerides (TGs) and is present in 75–90% of subjects with type 2 diabtes [9, 10]. NAFLD may progress to the more severe condition of NASH, characterized by advanced histological remodeling including fibrosis, lobular inflammation, hepatocellular ballooning, and risk of liver cancer. Since numerous pathways including insulin resistance, lipotoxicity, oxidative stress, immunology, the cytokine system, mitochondrial damage, and apoptosis are involved in the pathophysiology of NASH, various pharmacotherapies are being developed. Although no presently available drugs can be recommended for evidence-based treatment of NASH, antidiabetic drugs may prove useful in patients with comorbid diabetes mellitus.
We found that OMG appears to offer benefits for NAFLD patients along with decreased insulin resistance and inflammation. Based on this experience, we tried OMG on a NASH patient in whom glycemic control, liver function, and hepatic fibrosis markers improved markedly, along with decreased HOMA-IR and hsCRP, and improvements in intrahepatic fat deposition and fibrosis were seen on diagnostic imaging.
DPP4 has been linked to hepatic insulin sensitivity in several studies. Thus, in mice, hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis [6], whereas knockdown of DPP4 improves insulin sensitivity and reduces lipid accumulation in cultured hepatocytes [11]. Other studies have pointed toward DPP4 acting as a hepatokine, linking the liver and adipose tissue with the development of insulin resistance, and glucose intolerance. In mice, obesity and the associated visceral adipose tissue inflammation result in insulin resistance, a process that appears to be mediated via increased synthesis and release of hepatic DPP4, since eliminating hepatocyte DPP4 expression suppresses inflammation and improves insulin sensitivity [4, 12]. The mechanism seems independent of the catalytic activity of DPP4, since these effects were not mimicked by systemic daily DPP4 inhibition [4, 12]. On the other hand, the inhibition of the catalytic activity of DPP4 with DPP4 inhibitors was suggested to be, at least partially, involved since insulin signaling was improved following inclusion of DPP4 inhibitors in adipocytes in culture, but the DPP4 substrates mediating the effect remained unidentified [13, 14].
The issue of why weekly OMG shows beneficial effects against NAFLD/NASH where daily DPP4 inhibitors do not might be attributable to the concentration of molecules under the condition. The activity of daily DPP4 inhibitors is evaluated by inhibition of the ability of DPP4 serine exopeptidase to inactivate incretins in the blood. The concentration of daily DPP4 inhibitors in organs including the liver thus appears very low while insulin-stimulated activation of Akt is augmented by sitagliptin and saxagliptin in adipocytes in culture where cells are exposed to certain concentrations of DPP4 inhibitors [13, 14]. On the other hand, OMG after single oral administration continues to be detected in the mouse liver for 1 week [8].
DPP4 is proposed to represent a novel adipokine that may impair insulin sensitivity in autocrine and paracrine fashions [13]. DPP4 release strongly correlates with adipocyte size, potentially representing an important source of DPP4 [13]. The greater the fat content in the liver, the greater the expression/secretion of hepatokine DPP4, which might lead to NAFLD, and then to NASH. OMG might thus block the activity of DPP4 highly secreted from the liver under conditions of NAFLD/NASH, averting the promotion of adipose inflammation and insulin resistance in autocrine and paracrine fashions.
Accordingly, excess DPP4 derived from adipocytes and/or hepatocytes may act as a local mediator of inflammation and adipose/hepatic tissue insulin resistance, thereby forming a link between obesity and the pathogenesis of tpe2 diabetes and metabolic disease. Sodium-glucose transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists have recently shown potential efficacy for the treatment of NAFLD/NASH with diabetes [1, 15, 16], but are expected to be more effective for NAFLD/NASH in obese diabetic patients. The effects of OMG in decreasing intrahepatic fat accumulation and improving intrahepatic adipose inflammation are expected to be helpful for the treatment of NAFLD/NASH, particularly in non-obese, insulin-resistant, diabetic patients.
The limitations of the present study were the relatively small number of participants. Since this is a novel possible therapeutics for NAFLD/NASH complicated with diabetes, long-term assessments of large number of patients would be necessary.