**5. Placenta-derived drugs Laennec (i.v) and Porcine (oral) are capable of improving T2DM complicating with NASH/NAFLD through the action of 'hepcidin inducer'**

The discovery of hepcidin and its role in iron metabolism could lead to novel therapies for hereditary hemochromatosis and other iron-loading diseases. Laennec (parenteral) and Porcine (oral), which are hepcidin inducers, actually improved iron overload in a hereditary hemochromatosis patient, without performing sequential phlebotomy. This suggests the possibility of not only improving the prognosis of hereditary hemochromatosis but also ameliorating complications, such as type 2 diabetes, liver fibrosis and hypogonadism. Laennec and Porcine can completely replace continuous venesection in patients with hereditary hemochromatosis and may improve other iron-overloading disorders caused by hepcidin deficiency and/or insufficiency [73, 75] (**Figures 1**–**4**).

The association with hepcidin is supposed in many kinds of human diseases, furthermore, most of these diseases are influenced by alterations in hepcidin concentrations [73, 76]. Hepcidin-targeted therapies may improve the manifestations and biochemical abnormalities of patients with iron disorders. Although no specific hepcidin therapies are currently available, several compounds are under development as hepcidin agonists or antagonists [77]. Moreover, hepcidin either has a primary or a secondary role in insulin resistance, which is a characteristic of T2DM. However, it remains inconclusive whether serum hepcidin levels are an independent risk factor in the etiopathogenesis of T2DM. By inducing preferable and appropriate amounts of hepcidin, placenta-derived drugs could improve the clinical course of NASH complicated with T2DM and hyperferritinemia by attenuating

**Figure 3.**

*H. hemochromatosis treated with Laennec and porcine. Case, 47-year-old male. For 74 months, only Laennec (6A/d, 3/w) and porcine have been utilised effectively without phlebotomy. 67,200 ml (33,600 mg Fe) of phlebotomy were exempted: Estimated ferritin elevation 23,312 ng/ml (47/100 ml phlebotomy). Actually only 66.8 ng/ml elevated (0.28% of estimated ferritin elevation).*

### **Figure 4.**

*After treatment with Laennec without phlebotomy for 84 months, the histological evaluation revealed a remarkable reduction in iron deposition and fibrosis. At the same time, remarkable improvements in the quality of life (QOL) and erectile dysfunction (ED) were observed. During these periods, oral administration with porcine was replaced with Laennec for 8 months; however, the efficacy remained the same.*

the iron-induced oxidative stress and iron accumulation in both hepatocytes and pancreatic β-cells [78].

It is generally confirmed that iron overload causes insulin deficiency by promoting pancreatic β-cell apoptosis. Because of their stringent dependence on mitochondrial glucose metabolism and their limited antioxidant capacity [79], β-cells are extremely susceptible to oxidative stress. Through their divalent metal transporter, pancreatic β-cells can avariciously take up non-Tf-bound iron [80], which can promote oxidative stress by catalysing the Fenton reaction. Elevated iron levels oxidise various biomolecules, such as nucleic acids, proteins, and lipids, which may contribute to the development of T2DM by decreasing the insulin secretion from pancreatic β-cells, with a concomitant increase in insulin resistance [14, 76].

In our clinical data: Laennec has been administered [73] (**Figures 3** and **4**) to a patient with hereditary hemochromatosis without phlebotomy. HbA1c levels have further improved by Laennec treatment (more than 2% declined) for 84 months without changing the medications for diabetes treatment. These results are probably due to the additive efficacy of Laennec in reducing iron-originated ROS, enhancing the antiinflammatory action with concomitant improvement in liver fibrosis, and diminishing the iron deposition in hepatocytes. Laennec was also administered to patients with NASH with T2DM (**Figures 5**–**8**); treatment with Laennec significantly improved the T2DM, reduced the serum ferritin level, and decreased the iron deposition in the hepatocytes [73, 74]. The regulation of iron and glucose metabolism is possibly due to the pancreatic β-cells' ability to co-release insulin and hepcidin.

The data published by Kulaksiz et al. [81] demonstrated that hepcidin is expressed in the pancreas of rats and humans. Further analysis showed that it was localised in the β-cells of the islets of Langerhans. In addition, in vitro experiments performed

### **Figure 5.**

*Type 2 diabetes mellitus complicating with NASH grade 2, stage 2, 58 years old female. H.P.I: she has been followed up with the diagnosis of type 2 DM, SAS, hypertension and liver dysfunction (fatty liver) for these 5 years by a diabetologist. HBsAg (−) HCV (−) the control type 2 DM has been actually not so preferable (HbA1c 7.5–9.0%) BW 84.1 kg, HT 84.1 kg, HT 165.0 cm, BMI 30.9. As for SAS: CPAP tx continuing drugs for DM: sitagliptin 50 mg/d reduced to 25 mg after Laennec Tx.*

### **Figure 6.**

*The histological evaluation revealed the presence of fatty metamorphosis, inflammation, pericellular fibrosis, ballooning of hepatocyte, Mallory body and iron deposition mainly in the hepatocyte. After treating with Laennec, the histological evaluation revealed remarkable improvement in iron deposition and fibrosis, as well as amelioration of inflammation and fatty metamorphosis.*
