Hae Jin Kim

Background. Inflammation is a major cause of hepatic tissue damage and accelerates the progression of nonalcoholic fatty liver disease (NAFLD). Amphiregulin (AREG), an epidermal growth factor receptor ligand, is associated with human liver cirrhosis and hepatocellular carcinoma. We aimed to investigate the effects of AREG on hepatic inflammation during NAFLD progression, in vivo and in vitro. Methods. AREG gene expression was measured in the liver of mice fed a methionine choline-deficient (MCD) diet for 2 weeks. We evaluated inflammatory mediators and signaling pathways in HepG2 cells after stimulation with AREG. Nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were analyzed using an enzyme-linked immunosorbent assay and western blotting. Nuclear transcription factor kappa-B (NF-κB) and mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase, were analyzed using western blotting. Results. Proinflammatory cytokines (interleukin (IL)-6, IL-1β, and IL-8) and immune cell recruitment (as indicated by L3T4, F4/80, and ly6G mRNA expression) increased, and expression of AREG increased in the liver of mice fed the MCD diet. AREG significantly increased the expression of IL-6 and IL-1β and the production of NO, PGE2, and IL-8 in HepG2 cells. It also activated the protein expression of iNOS and COX-2. AREG-activated NF-κB and MAPKs signaling, and together with NF-κB and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2. Conclusion. AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-κB and MAPKs signaling.

OBJECTIVE The natural course of diabetes of the exocrine pancreas (DEP) is not well established. We aimed to compare the risk of insulin initiation, diabetic complications, and mortality between DEP and type 2 diabetes. RESEARCH DESIGN AND METHODS Using the Korean National Health Insurance Service–Health Screening Cohort between 2012 and 2017, we divided patients with diabetes into those with diabetes without prior pancreatic disease (indicated type 2 diabetes, n = 153,894) and diabetes with a prior diagnosis of pancreatic disease (indicated DEP, n = 3,629). ICD-10 codes and pharmacy prescription information were used to define type 2 diabetes, DEP, and acute and chronic diabetes complications. Kaplan-Meier curves were produced to compare insulin use over time between groups. We created logistic regression models for odds of progression to diabetic complications and mortality. RESULTS DEP was associated with a higher risk of insulin use than type 2 diabetes (adjusted hazard ratio 1.38 at 5 years [95% CI 1.30–1.47], P < 0.0001). Individuals with DEP showed higher risks of hypoglycemia (odds ratio 1.85 [1.54–2.21], P < 0.0001), diabetic neuropathy (1.38 [1.28–1.49], P < 0.0001), nephropathy (1.38 [1.27–1.50], P < 0.0001), retinopathy (1.10 [1.01–1.20], P = 0.0347), coronary heart disease (1.59 [1.48–1.70], P < 0.0001), cerebrovascular disease (1.38 [1.28–1.49], P < 0.0001), and peripheral arterial disease (1.34 [1.25–1.44], P < 0.0001). All-cause mortality was higher in those with DEP (1.74 [1.57–1.93], P < 0.0001) than in those with type 2 diabetes. CONCLUSIONS DEP is more likely to require insulin therapy than type 2 diabetes. Hypoglycemia, micro- and macrovascular complications, and all-cause mortality events are higher in DEP compared with type 2 diabetes.