Cirrhosis is as a late stage of scarring (fibrosis) of the liver caused by liver diseases and conditions, such as hepatitis B virus (HBV)-induced cirrhosis, alcoholic cirrhosis, schistosomiasis-induced cirrhosis, metabolic cirrhosis, cholestasis cirrhosis, and cirrhosis of unknown etiology, and the most common type is HBV-induced cirrhosis in China (Chang et al., 2017). If no timely and effective antiviral treatment is provided for HBV-induced cirrhosis, it often progresses quickly to the stage of cirrhosis. In the late stage, serious complications, including decreased hepatic functional capacity, ascites, gastrointestinal bleeding, and even hepatic encephalopathy may occur. The liver is an important metabolic organ, and its metabolic activity is controlled by insulin and other metabolic hormones. Cirrhosis and diabetes are a two-way mutually-promoting process. Cirrhosis leads to abnormal glucose metabolism, and the elevated blood glucose level enhances damage to liver function and forms a vicious circle. Clinical treatment for cirrhosis is a highly complicated process (Xu et al., 2019; Michel et al., 2020), seriously influencing the quality of life and health of patients with cirrhosis.

The underlying mechanism of diabetes that contributes to cirrhosis is more complicated, and it is clinically manifested as insulin resistance (IR) and hyperinsulinemia. The underlying mechanism could be summarized as follows (Li et al., 2019): (I) In patients with liver cirrhosis, due to liver fatty degeneration and inflammatory damage, insulin receptors in the liver, muscles, pancreas, and other tissues decrease, and insulin affinity reduces, which in turn causes IR. At the same time, impaired liver function causes inactivation of liver glycogen synthase, hexokinase, glucokinase, growth hormone, and other obstacles, thereby leading to an abnormal glycogen synthesis and the increased gluconeogenesis (Kumar, 2018); (II) The decreased hepatic insulin clearance may result in peripheral hyperinsulinemia, because the liver function in patients with liver cirrhosis reduces and portosystemic shunts increase. Due to the long-term stimulation of hyperglycemia, secretion of compensatory insulin from pancreatic islet β cells increases in the early stage, and dysfunction of pancreatic islet β cells may occur in the later stage, and then, develops into diabetes (Grancini et al., 2015); and (III) In addition, it may also be associated with hepatitis viruses (types C and D) and toxic effects, including immune complexes, degeneration of pancreatic islet β cells, electrolyte imbalance, leptin resistance, genetic inheritance, and other factors (Elkrief et al., 2016). Type 2 diabetes mellitus (T2DM) could promote the development of hepatitis cirrhosis, increase the incidence of associated complications, and enhance the occurrence of liver cancer (Su et al., 2015). Diabetes is an independent risk factor for primary liver cancer, and is associated with HBV, hepatitis C virus (HCV), and alcoholic liver disease, leading to increase the risk of liver cancer (Dankner et al., 2016). Therefore, how to effectively block the vicious circle between cirrhosis and diabetes is the key to the treatment of diabetic patients with cirrhosis.

The most appropriate treatment strategy for decompensated liver cirrhosis (DLC) is orthotopic liver transplantation. However, due to the shortage of donors, complicated surgery, remarkable expenses, and the long-term use of immunosuppressants, its clinical application is limited. Cell therapy includes hepatocyte transplantation and stem cell therapy, both of which are theoretically feasible (Sheykhhasan, 2019). Hepatocytes have the ability to regenerate, and a number of scholars theoretically pointed out that hepatocyte transplantation should be able to restore the liver function after liver cirrhosis treatment. However, hepatocytes’ viability under in vitro cryopreservation decreases, which limits their clinical application to a certain extent (Komolkriengkrai et al., 2019). Stem cells are a type of cells with multiple differentiation potentials, and can differentiate into different cells in various environments. With the rapid development of stem cell research, stem cell transplantation has markedly attracted clinicians’ attention to treat cirrhosis (Memon and Abdelalim, 2020). Bone marrow-derived stem cells (BMSCs) are the main extrahepatic source of hepatocytes. BMSCs can differentiate into hepatic stem cells and hepatocytes under specific circumstances, and then, repair the liver function (Bihari et al., 2016). In our previous study, we used autologous bone marrow cell infusion (ABMI) via an infusion port through the right omental vein (ROV) to achieve a significant therapeutic efficacy (Liu et al., 2013). A number of patients even stopped taking oral hypoglycemic drugs. Although the treatment of liver cirrhosis has been found to have a certain improvement effect on diabetes, if we inject autologous bone marrow through the right omental artery (ROA) directly on the pancreas, whether it is more effective or not requires further research. Based on the above-mentioned clinical findings, our team, in this research, embedded the infusion port through the ROA and ROV, collected autologous bone marrow (ABM), performed infusion via the ROA and ROV, and attempted to indicate whether it could further improve the treatment efficacy for DLC patients with T2DM.

Decompensated liver cirrhosis is defined as an acute deterioration in liver function in patients with cirrhosis and is characterized by jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage, while no effective therapy has been presented for DLC yet (Bernardi and Caraceni, 2018). Although liver transplantation has shown to be clinically significant for liver cirrhosis, its clinical application has been limited due to the serious shortage of donors and remarkable expenses. In recent years, several studies have reported that BMSCs could be effective for the repair of liver function (Liu et al., 2014; Pan et al., 2014), and this finding has also been confirmed in animal models. In addition, a limited number of clinical studies showed that transplantation of BMSCs could quickly improve the liver function without obvious adverse effects (Wu et al., 2019; Sun et al., 2020), indicating the lack of a multi-center and systematic research and the absence of an effective treatment plan for liver cirrhosis (Esmaeilzadeh et al., 2019). In the present study, the levels of ALB, TB, PT, and ascites were significantly elevated in the two groups at 1month after treatment, suggesting that the hepatic synthesis and secretion function were significantly improved. With the elevation of ALB level, the colloid osmotic pressure increased, the degree of liver cirrhosis and portal pressure decreased, and the amount of ascites was gradually reduced. After 3–4 times of ABMI through the portal vein, the liver function was significantly improved after 1year of follow-up, and the liver function partly returned to normal. It is well known that there are a variety of stem cells and cytokines in the bone marrow. Treatment via ABMI can promote the repair of liver function in patients with cirrhosis. Stem cells have the potential to differentiate into a variety of cells affected by certain factors in different microenvironments, and they can also produce certain cytokines to promote the repair of damaged cells (Zhang et al., 2012; Liu et al., 2013). The treatment mechanism of BMSCs for cirrhosis was previously described as follows (Zhang and Wang, 2013): (I) On the one hand, the hepatocyte-like BMSCs could be transferred into the liver parenchyma under the stimulation of the microenvironment; on the other hand, they could differentiate into liver oval cells, and they could be directly differentiated into liver parenchymal cells, hepatic stellate cells, and myofibroblasts. The hepatic oval cells were discovered by Farber when he was studying the pathology of liver tumors. They were named as oval cells because they were oval-shaped cells. There are few oval cells in the adult liver, which are mainly distributed around the portal vein at rest. When the liver is stimulated by pathogenic factors, the existing oval cells and newly formed oval cells can be differentiated into hepatocytes, bile duct cells, etc., due to the changes in the microenvironment and stimulation of cytokines (Farber, 1956); (II) Improving the microenvironment through paracrine when BMSCs can be entered the liver, whether there is cell differentiation or anti-liver fibrosis, they are inseparable from various cytokines and inflammatory mediators. The cytokines and inflammatory mediators could activate liver progenitor cells, thereby inhibiting the activation of stellate cells and promoting their apoptosis, as well as inhibiting the proliferation and migration of inflammatory cells at the injury site (Suh et al., 2012). In the present study, it was shown that the liver function was improved in DLC patients with T2DM, while the difference between the two groups was not statistically significant, indicating that the ABMI through the ROA did not improve the liver function.

Under fasting conditions, the liver plays a major role in generating glucose as a fuel for other tissues, such as brain, red blood cells, and muscles. Normally, stored glycogen is critical for maintaining glucose homeostasis in mammals during an overnight fasting period. Therefore, there is an inseparable association between the occurrence of liver disease and glucose metabolism disorders. Globally, the incidence of diabetes was estimated about 1% in healthy individuals (Quist-Therson et al., 2020). The incidence of diabetes was significantly elevated in patients with chronic liver dysfunction, especially in patients with liver cirrhosis, in which more than 80% of patients had impaired glucose tolerance, and 40–50% of patients were at a high risk of developing diabetes (Petit et al., 2014; Grancini et al., 2015). Therefore, it is vital for patients with hepatogenic diabetes to receive clinical attention and proactive treatment (Zhang et al., 2019). In the current study, ABMI was performed only via the ROV. After 1month, the liver function improved, and the serum FBG and HbA1c levels decreased, which is consistent with the finding of a previous research, in which a successful stem cell therapy for chronic liver cell failure patients could improve T2DM by increasing IR (Haydara et al., 2019). However, with the continuously infusion of ABM through the portal vein, as the liver function continued to improve, the serum FBG and HbA1c levels did not significantly change, while more significant changes were observed in the observation group, suggesting that the main reason for increasing the serum FBG levels was not related to the liver function, and pancreatic islet dysfunction in patients with liver cirrhosis and diabetes is a more important factor. The results of the current research revealed that the amount of insulin used in the observation group was significantly lower than that in the control group before ABMI, indicating that ABMI via ROV did not significantly reduce the amount of insulin, implying that it did not improve the physiological function of islet β cells. ABM was used to infuse through the ROA, BMSCs could enter the pancreas through the ROA, BMSCs might be transformed into islet β cells, or secrete certain cytokines to promote the repair and reconstruction of damaged islet β cells, and the regulatory function of blood glucose could be improved. If the ABMI was infused only through the portal vein, some stem cells might return to the right atrium and right ventricle through the hepatic vein. After the pulmonary circulation, they could enter the systemic circulation, and a limited number of stem cells might enter the pancreas. Because the number of stem cells was extremely small, the performance of islet β cells slightly improved, while ABMI through the ROA significantly improved the performance of islet β cells compared with the ROV infusion alone. This also suggested that the infusion of BMSCs into the liver tissue with cirrhosis could repair the damaged hepatocytes, leading to improve the liver function, and the infusion of BMSCs into the pancreas could repair the damaged islet β cells. The microenvironment with the cell damage in different organs could promote the transformation of BMSCs into different cells or secrete certain factors to promote the functional recovery of injured organs.

In summary, the ABMI via ROV and ROA showed noticeable effects on the treatment of DLC patients with T2DM. The ABMI via the ROV did not significantly improve diabetes, while ABMI via the ROA did not remarkably improve the liver function.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Shanghai Public Health Clinical Center Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

BL conceived and designed the experiments. MC and LLa performed this experimental work and analyzed the data. LLi, YS, and GW participated in the experiments. All authors contributed to the article and approved the submitted version.

This study was financially supported by Shanghai Shenkang Hospital Development Center (Grant No. SHDC12016129) and Scientific Research Project of Shanghai Municipal Health Commission (Grant No. 201940430).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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