Takumi Kawaguchi

Branched‐chain amino acids as pharmacological nutrients in chronic liver disease

Branched‐chain amino acids (BCAAs) are a group of essential amino acids comprising valine, leucine, and isoleucine. A low ratio of plasma BCAAs to aromatic amino acids is a physiological hallmark of liver cirrhosis, and BCAA supplementation was originally devised with the intention of normalizing amino acid profiles and nutritional status. However, recent studies on BCAAs have revealed that, in addition to their role as protein constituents, they may have a role as pharmacological nutrients for patients with chronic liver disease. Large‐scale, multicenter, randomized, double‐blinded, controlled trials on BCAA supplementation have been performed in Italy and Japan, and results demonstrate that BCAA supplementation improves not only nutritional status, but also prognosis and quality of life in patients with liver cirrhosis. Moreover, accumulating experimental evidence suggests that the favorable effects of BCAA supplementation on prognosis may be supported by unforeseen pharmacological actions of BCAAs. This review summarizes the possible effects of BCAAs on albumin synthesis and insulin resistance from clinical and basic viewpoints. We also review the newly discovered clinical impact of BCAAs on hepatocellular carcinoma and the prognosis and quality of life of patients with liver cirrhosis. (HEPATOLOGY 2011;)

Association of exogenous insulin or sulphonylurea treatment with an increased incidence of hepatoma in patients with hepatitis C virus infection.

Background: Diabetes mellitus is frequently seen in hepatitis C patients and is often treated with antidiabetic agents that increase serum insulin levels. Because insulin is a growth‐promoting hormone, antidiabetic agents could pose a risk for hepatocellular carcinoma (HCC).

Insulin resistance and chronic liver disease.

Increased insulin resistance is frequently associated with chronic liver disease and is a pathophysiological feature of hepatogenous diabetes. Distinctive factors including hepatic parenchymal cell damage, portal-systemic shunting and hepatitis C virus are responsible for the development of hepatogenous insulin resistance/diabetes. Although it remains unclear whether insulin secretion from pancreatic beta cells is impaired as it is in type 2 diabetes, retinopathic and cardiovascular risk is low and major causes of death in cirrhotic patients with diabetes are liver failure, hepatocellular carcinoma and gastrointestinal hemorrhage. Hemoglobin A1c is an inaccurate marker for the assessment and management of hepatogenous diabetes. Moreover, exogenous insulin or sulfonylureas may be harmful because these agents may promote hepatocarcinogenesis. Thus, pathogenesis, cause of death, assessment and therapeutic strategy for hepatogenous insulin resistance/diabetes differ from those for lifestyle-related type 2 diabetes. In this article, we review features of insulin resistance in relationship to chronic liver disease. We also discuss the impact of anti-diabetic agents on interferon treatment and hepatocarcinogenesis.

Altered expression of glucagon‐like peptide‐1 and dipeptidyl peptidase IV in patients with HCV‐related glucose intolerance

Background and Aim:u2002 The pathogenesis of hepatitis C virus (HCV)‐associated glucose intolerance remains unclear. Glucagon‐like peptide‐1 (GLP‐1), a gut hormone, synthesizes hepatic glycogen and is inactivated by dipeptidyl peptidase IV (DPPIV). The aims of this study were to investigate the alterations in the expression of GLP‐1 and DPPIV in HCV‐associated glucose intolerance.

Hybrid training of voluntary and electrical muscle contractions reduces steatosis, insulin resistance, and IL-6 levels in patients with NAFLD: a pilot study

BackgroundPhysical inactivity is a risk factor for the development of non-alcoholic fatty liver disease (NAFLD). “Hybrid training”, a training that involves both voluntary and electrical muscle contractions, causes beneficial alterations in muscles even after short durations of exercise. The aim of this study was to investigate the therapeutic efficacy of hybrid training in patients with NAFLD.MethodsThirty-five patients with NAFLD who were resistant to lifestyle counseling were assigned to a hybrid-training group (nxa0=xa012) or a control group (nxa0=xa023). In the hybrid-training group, quadriceps and hamstrings were contracted voluntarily or electrically for 19xa0min twice a week. In the control group, patients received lifestyle counseling. The therapeutic efficacy of the hybrid training was evaluated after 12xa0weeks of the intervention.ResultsSerum alanine aminotransferase (ALT) levels and hepatic steatosis grade were significantly decreased in the hybrid-training group compared to that of the control group (−14.1xa0±xa05.8 vs. 3.5xa0±xa05.4xa0IU/mL; Pxa0<xa00.05, −0.67xa0±xa00.19 vs. 0.09xa0±xa00.06 grade; Pxa0<xa00.01, respectively). No significant changes were seen between the two groups in skeletal muscle mass. The decreases in homeostasis model assessment of insulin resistance (HOMA-IR) value and in serum IL-6 levels were significantly greater in the hybrid-training group than in the control group (−6.2xa0±xa03.2 vs. 0.4xa0±xa00.6; Pxa0<xa00.05, −3.1xa0±xa01.1 vs. 1.1xa0±xa00.5xa0pg/mL; Pxa0<xa00.01, respectively).ConclusionHybrid training of voluntary and electrical muscle contractions improved hepatic steatosis and reduced insulin resistance and serum IL-6 levels in NAFLD patients who are resistant to lifestyle counseling.

Total and high molecular weight adiponectin and hepatocellular carcinoma with HCV infection.

Background Adiponectin is shown to be inversely associated with development and progression of various cancers. We evaluated whether adiponectin level was associated with the prevalence and histological grade of hepatocellular carcinoma (HCC), and liver fibrosis in patients with hepatitis C virus (HCV) infection. Methods A case-control study was conducted on 97 HCC patients (cases) and 97 patients (controls) matched for sex, Child-Pugh grade and platelet count in patients with HCV infection. The serum total and high molecular weight (HMW) adiponectin levels were measured by enzyme-linked immunosorbent assays and examined in their association with the prevalence of HCC. In addition, the relationship between these adiponectin levels and body mass index (BMI), progression of liver fibrosis, and histological grade of HCC was also evaluated. Liver fibrosis was assessed using the aspartate aminotransferase to platelet ratio index (APRI). Results There were no significant differences in the serum total and HMW adiponectin levels between cases and controls. Moreover, there were no inverse associations between serum total and HMW adiponectin levels and BMI in both cases and controls. On the other hand, serum total and HMW adiponectin levels are positively correlated with APRI in both cases (ru200a=u200a0.491, P<0.001 and ru200a=u200a0.485, P<0.001, respectively) and controls (ru200a=u200a0.482, P<0.001 and ru200a=u200a0.476, P<0.001, respectively). Interestingly, lower serum total (OR 11.76, 95% CI: 2.97–46.66 [P<0.001]) and HMW (OR 10.24, CI: 2.80–37.40 [P<0.001] adiponectin levels were independent risk factors of worse histological grade of HCC. Conclusions Our results suggested that serum total and HMW adiponectin levels were predictors of liver fibrosis, but not prevalence of HCC in patients with HCV infection. Moreover, low these adiponectin levels were significantly associated with worse histological grades.

Branched-Chain Amino Acids and Pigment Epithelium-Derived Factor: Novel Therapeutic Agents for Hepatitis C Virus-Associated Insulin Resistance

Recent clinical studies have shown that patients with chronic liver disease are insulin resistant. Of all etiologies of chronic liver disease including non-alcoholic fatty liver disease, the one that causes the most sever insulin resistance is hepatitis C virus (HCV) infection. Since insulin resistance promotes inflammatory and fibrogenic reactions in the liver, thus leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC) in patients with HCV infection, amelioration of insulin sensitivity may inhibit the progression of HCV-associated liver disease, and could improve the survival of these patients. HCV directly causes insulin resistance through HCV core protein-elicited proteasomal degradation of insulin receptor substrates and subsequent inactivation of intracellular insulin signaling molecules such as Akt. Furthermore, tumor necrosis factor-alpha (TNF-alpha) and/or triglyceride accumulation-induced nuclear factor-kappaB (NF-kappaB) activation in the liver is shown to play a role in insulin resistance in patients with HCV-related chronic liver disease as well. We, along with others, have recently found that branched-chain amino acids (BCAAs) and pigment epithelium-derived factor (PEDF) could improve the HCV-associated insulin resistance via suppression of NF-kappaB and preservation of insulin signaling pathway. In this review, we discuss the mechanisms for the actions of BCAAs and PEDF, and their clinical implications in insulin resistance of chronic liver disease in patients with HCV infection. We also discuss here which chemical structures could contribute to insulin-sensitization in patients with HCV infection.

Pigment Epithelium-Derived Factor Inhibits Lysosomal Degradation of Bcl-xL and Apoptosis in HepG2 cells

Pigment epithelium-derived factor (PEDF) has several biological actions on tumor cells, but its effects are cell-type dependent. The aim of this study was to examine the pathophysiological role of PEDF in hepatocellular carcinoma (HCC). PEDF expression was examined in various hepatoma cell lines and human HCC tissues, and was seen in various hepatoma cell lines including HepG2 cells. In human HCC tissues, PEDF expression was higher than in adjacent non-HCC tissues. In addition, serum PEDF levels were higher in HCC patients than in non-HCC patients, and curative treatment of HCC caused significant reductions in serum PEDF levels compared with pretreatment levels. In vitro experiments, camptothecin (CPT) was used to induce apoptosis and the effect of PEDF was investigated by knockdown of the PEDF gene in CPT-treated HepG2 cells. Knockdown of the PEDF gene enhanced CPT-induced apoptosis, simultaneously down-regulating Bcl-xL expression in HepG2 cells. Expression of apoptosis-related molecules and effects of bafilomycin A1 on CPT-induced apoptosis were also examined in PEDF gene knockdown HepG2 cells. Treatment with bafilomycin A1 suppressed CPT-induced decreases in Bcl-xL expression and increases in apoptosis in PEDF gene knockdown HepG2 cells. PEDF may, therefore, exert anti-apoptotic effects through inhibition of lysosomal degradation of Bcl-xL in CPT-treated HepG2 cells.

Hybrid training of voluntary and electrical muscle contractions decreased fasting blood glucose and serum interleukin-6 levels in elderly people: a pilot study

A new muscle-training method, hybrid training, utilizing combined voluntary and electrical muscle contractions, is effective for increasing muscle mass and force on lower extremities in elderly people. Although skeletal muscle regulates glucose metabolism, partly by releasing interleukin (IL)-6, the effects of hybrid training on glucose metabolism remains unclear. The aim of this study was to investigate the effects of hybrid training on glucose metabolism and serum IL-6 levels in elderly people. Hybrid training was performed on 7 elderly subjects. Both quadriceps and hamstrings were contracted voluntarily or electrically at the same time for 19xa0min twice a week. The effects on glucose metabolism and serum IL-6 levels were evaluated after 12xa0weeks of hybrid training. All of the subjects completed the study, and no severe adverse events developed during the study period. There were no significant differences in body mass index, serum insulin levels, homeostasis model assessment for insulin resistance values, or hemoglobin A1c values after hybrid training. However, fasting blood glucose levels were significantly decreased after hybrid training (114xa0± 13 vs. 103xa0± 9xa0mg·dL(-1); p = 0.0340). In addition, all 7 subjects showed a decrease in serum IL-6 levels after hybrid training, and this decrease was statistically significant (44.0xa0± 35.6 vs. 14.6xa0± 10.5 pg·mL(-1); p = 0.0180). Furthermore, there was a significant correlation between changes in serum IL-6 levels and changes in fasting blood glucose levels (ρ = 0.883; p = 0.0306). In this study, we showed the safety and good adherence of hybrid training for lower extremities in elderly people. Furthermore, hybrid training decreased fasting blood glucose and serum IL-6 levels in elderly people.

The Pathogenesis, Complications and Therapeutic Strategy for Hepatitis C Virus-associated Insulin Resistance in the Era of Anti-viral Treatment

Recent experimental and clinical studies have shown that chronic hepatitis C virus (HCV) infection causes insulin resistance. Since insulin resistance decreases response to antiviral treatments, promotes inflammatory and fibrogenic reactions and increases a risk of hepatocellular carcinoma (HCC), amelioration of insulin resistance may be a novel therapeutic target, which could improve the prognosis in patients with HCV-related chronic liver disease. Despite the increased awareness of health risk of insulin resistance, there is no common therapeutic strategy for HCV-associated insulin resistance. Indeed, treatments with exogenous insulin or sulfonylureas may be rather harmful because these treatments are associated with the development of HCC in patients with HCV infection. Meanwhile, we, along with others, have found distinctive treatments which improve HCV-associated insulin resistance. Administration of branched-chain amino acids (BCAA), especially as a late evening snack, improves glucose metabolism by improving insulin-signal cascades in insulin resistance patients with HCV infection. In this paper, we discuss the pathogenesis and complications for HCV-associated insulin resistance and further review a recent clinical therapeutic strategy using these agents for the treatment of this devastating disorder. We also discuss therapeutic potentialities of incretin-based therapies, new anti-diabetic agents for HCV-associated insulin resistance and the significance of insulin resistance in the era of new anti-viral treatments.