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

Itou, Minoru; Kawaguchi, Takumi; Taniguchi, Eitaro; Sumie, Shuji; Oriishi, Tetsuharu; Mitsuyama, Keiichi; Takahashi, Osamu; Ueno, Takato; Sata, Michio

doi:10.1111/j.1440-1746.2007.05183.x

Cited by 48 publications

(45 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Serum DPP4 activity was significantly higher in patients with chronic hepatitis C virus (HCV) infection and primary biliary cirrhosis than in healthy controls (16,17). Increased DPP4 protein was also detected in the ileum and liver in HCV-infected patients (18). In animal models, elevated serum DPP4 activity was observed in rat cirrhosis induced by diethyl-nitrosamine, phenobarbital and carbon tetrachloride, and was positively correlated with serum transaminase levels (19).…”

Section: Discussionmentioning

confidence: 84%

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

et al. 2011

View full text Add to dashboard Cite

Abstract. Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cellmediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of nonalcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease. IntroductionNon-alcoholic fatty liver disease (NAFLD) is a clinicopathological disorder characterized by the accumulation of triglycerides in hepatocytes. The incidence of NAFLD has increased markedly in recent years, accompanying the increased prevalence of obesity and type 2 diabetes mellitus (T2DM) (1). More than 10% of patients with NAFLD progress to non-alcoholic steatohepatitis (NASH), which is characterized by inflammatory cell infiltration and ballooning of hepatocytes in the liver. Liver cirrhosis and hepatocellular carcinoma occur in several patients with NASH (2). Obesity and insulin resistance (IR) are believed to be involved in the pathogenesis of NAFLD (3). Increased hepatic uptake of fatty acids as a result of elevated triglyceride degradation in adipose tissue causes hepatic fat accumulation. Reactive oxygen species (ROS) produced during lipid oxidation may induce hepatocyte death and inflammatory reactions. IR also reduces glucose uptake in muscles and diminishes insulin-dependent suppression of gluconeogenesis, ultimately progressing to T2DM (4).Dipeptidyl peptidase-4 (DPP4) inhibitors were recently introduced for the treatment of T2DM (5). DPP4 degrades glucagon-like peptide-1 (GLP-1), which stimulates insulin secretion from pancreatic β-cells. DPP4 inhibitors enhance glucose-dependent insulin secretion by suppressing GLP-1 degradation. However, the physiological functions of DPP4 are not fully understood. In addition to its effect on GLP-1, multiple activities of DPP4 have been reported in various cellular processes. Of note, DPP4 seems to influence inflammation by regu...

show abstract

Section: Discussionmentioning

confidence: 84%

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Although changes in GLP-1 and DPP-4 remain unclear in hepatogenous insulin resistance, we previously investigated changes of these molecules in patients with HCV infection [124] . The serum level of the active GLP-1 in HCV-infected patients is significantly lower than that in hepatitis B virus-infected patients and healthy subjects.…”

Section: Dipeptidyl Peptidase-4 Inhibitorsmentioning

confidence: 99%

Insulin resistance and chronic liver disease

Kawaguchi

Taniguchi²,

Itou³

et al. 2011

WJH

Self Cite

View full text Add to dashboard Cite

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, portalsystemic 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.

show abstract

“…In addition to diet and exercise, insulin levels, insulin sensitivity and peripheral insulin resistance are important for glucose homeostasis, but their measurement and interpretation are complex; these indices are therefore more applicable in a research setting. 7 Itou and colleagues observed high serum DPIV levels in HCV patients, 3 a finding previously noted in other various inflammatory conditions. 8 DPIV inhibitory compounds developed in the 1980s suppress immune responses, 8 so when DPIV inhibition was first proposed as a type 2 diabetes therapy there was concern about therapeutic specificity.…”

mentioning

confidence: 67%

“…2 In this issue of the Journal of Gastroenterology and Hepatology, Itou and colleagues report that serum levels of the active form of GLP-1 are lowered in chronic hepatitis C and that DPIV levels are increased in the ileum and serum of those patients. 3 This observation points to a potential contribution of the DPIV-incretin axis to the mechanism of IGT in hepatitis C.…”

mentioning

confidence: 93%

“…3 The spectrum of liver disease, however, has changed over recent years. The development of sinusoidal obstruction syndrome (SOS) (previously known as veno-occlusive disease) is less common, with the recognition that the incidence can be reduced by the use of less intensive myeloablative regimens, fludarabine instead of cyclophosphamide and targeted busulfan dosing.…”

mentioning

confidence: 99%

See 1 more Smart Citation