OBJECTIVE: To explore the role of 5-hydroxytryptamine (5-HT) in type 2 diabetes mellitus (T2DM)-related hepatic inflammation and fibrosis. METHODS: Male C57BL/6J mice were used to establish T2DM model by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. Then, the mice with hyperglycemia were still fed with high-fat diet for nine weeks, and treated with or without 5-HT_2A receptor (5-HT_2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (alone or in combination). To observe the role of 5-HT in the myofibroblastization of hepa-tic stellate cells (HSCs), human HSCs LX-2 were exposed to high glucose, and were treated with or without SH, CDP or monoamine oxidase A (MAO-A) inhibitor clorgiline (CGL). Hematoxylin & eosin and Masson staining were used to detect the pathological lesions of liver tissue section, immunohistochemistry and Western blot were used to analyze protein expression, biochemical indicators were measured by ELISA or enzyme kits, and levels of intracellular reactive oxygen species (ROS) were detected by fluorescent probe. RESULTS: There were up-regulated expressions of 5-HT_2AR, 5-HT synthases and MAO-A, and elevated levels of 5-HT in the liver of the T2DM mice. In addition to reduction of the hepatic 5-HT levels and MAO-A expression, treatment with SH and CDP could effectively ameliorate liver lesions in the T2DM mice, both of which could ameliorate hepatic injury and steatosis, significantly inhibit the increase of hepatic ROS (H₂O₂) levels to alleviate oxidative stress, and markedly suppress the production of transforming growth factor β1 (TGF-β1) and the development of inflammation and fibrosis in liver. More importantly, there was a synergistic effect between SH and CDP. Studies on LX-2 cells showed that high glucose could induce up-regulation of 5-HT_2AR, 5-HT synthases and MAO-A expression, increase intracellular 5-HT level, increase the production of ROS, and lead to myofibroblastization of LX-2, resulting in the increase of TGF-β1 synthesis and production of inflammatory and fibrosis factors. The effects of high glucose could be significantly inhibited by 5-HT_2AR antagonist SH or be markedly abolished by mitochondrial 5-HT degradation inhibitor CGL. In addition, SH significantly suppressed the up-regulation of 5-HT synthases and MAO-A induced by high glucose in LX-2. CONCLUSION Hyperglycemia-induced myofibroblastization and TGF-β1 production of HSCs, which leads to hepatic inflammation and fibrosis in T2DM mice, is probably due to the up-regulation of 5-HT_2AR expression and increase of 5-HT synthesis and degradation, resulting in the increase of ROS production in mitochondria. Among them, 5-HT_2AR is involved in the regulation of 5-HT synthases and MAO-A expression.
Male ; Mice ; Humans ; Animals ; Hepatic Stellate Cells/pathology* ; Transforming Growth Factor beta1/pharmacology* ; Serotonin/metabolism* ; Reactive Oxygen Species/metabolism* ; Diabetes Mellitus, Type 2/complications* ; Hydrogen Peroxide/metabolism* ; Mice, Inbred C57BL ; Liver Cirrhosis/etiology* ; Hyperglycemia/pathology* ; Monoamine Oxidase/metabolism* ; Inflammation ; Glucose/metabolism* ; Cytidine Diphosphate/pharmacology*

The prevalence of diabetes mellitus (DM) and associated diseases such as cancers are substantially increasing worldwide. About 80% of the patients with pancreatic cancer have glucose metabolism alterations. This suggests an association between type 2 DM and pancreatic cancer risk and progression. There are hypotheses that show metabolic links between the diseases, due to insulin resistance, hyperglycemia, hyperinsulinemia, low grade chronic inflammation, and alteration in the insulin-insulin-like growth factor axis. The use of diabetes medications can influence the extent of carcinogenesis of the pancreas. This study briefly reviews recent literature on investigation of metabolic link of type 2 DM, risk of carcinogenesis of the pancreas and their association, as well as the current understanding of metabolic pathways implicated in metabolism and cellular growth. The main finding of this review, although there are discrepancies, is that according to most research long-term DM does not raise the risk of pancreatic cancer. The longest duration of DM may reflect hypoinsulinemia due to treatment for hyperglycemia, but recent onset diabetes was associated with increased risk for pancreatic cancer due to hyperinsulinemia and hyperglycemia. In conclusion, the review demonstrates that type 2 DM and the duration of diabetes pose a risk for pancreatic carcinogenesis, and that there is biological link between the diseases.
Diabetes Mellitus, Type 2/complications/epidemiology/metabolism/*pathology ; Humans ; Hyperglycemia/pathology ; Insulin/metabolism ; Insulin Resistance ; Insulin-Like Growth Factor I/metabolism ; Pancreatic Neoplasms/epidemiology/*etiology ; Risk Factors

PURPOSE: Studies have shown that diabetes mellitus (DM) is a risk factor for cardiovascular disease, including atrial fibrillation (AF); however, the clinical characteristics and prognostic impact of DM in patients with nonvalvular AF have not been well understood in China. MATERIALS AND METHODS: Included were 1644 consecutive patients with nonvalvular AF. Endpoints included all-cause mortality, cardiovascular mortality, stroke, major bleeding, and combined endpoint events (CEE) during a 1-year follow-up. RESULTS: The prevalence of DM was 16.8% in nonvalvular AF patients. Compared with non-diabetic AF patients, diabetic AF patients were older and tended to coexist with other cardiovascular diseases. Most patients with DM (93.5%) were eligible for anticoagulation, as determined by CHADS2 scores. However, only 11.2% of patients received anticoagulation. During a 1-year follow-up, the all-cause mortality and CEE rate in the DM group were significantly higher than those of the non-DM group, while the incidence of stroke was comparable. After multivariate adjustments, DM was still an independent risk factor for 1-year all-cause mortality [hazard ratio (HR)=1.558; 95% confidence interval (CI) 1.126-2.156; p=0.007], cardiovascular mortality (HR=1.615; 95% CI 1.052-2.479; p=0.028), and CEE (HR=1.523; 95% CI 1.098-2.112; p=0.012), yet not for stroke (HR=1.119; 95% CI 0.724-1.728; p=0.614). CONCLUSION: DM is a common morbidity coexisting with nonvalvular AF and is associated with an increased risk of 1-year all-cause mortality, cardiovascular mortality, and CEE. However, no increased risk of stroke was found during a 1-year follow-up in patients with AF and DM.
Aged ; Atrial Fibrillation/*etiology ; Cause of Death ; China ; Diabetes Complications/*pathology ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Male ; Multivariate Analysis ; Proportional Hazards Models ; Risk Factors ; Treatment Outcome

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether patients with cryptogenic HCC share clinical features similar to that of NAFLD. METHODS: Cryptogenic HCC was defined as HCC that occurs in patients with the following conditions: HBsAg(-), anti-HCV(-), and alcohol ingestion of less than 20 g/day. All patients diagnosed with cryptogenic HCC from 2005 to 2012 (cryptogenic HCC group), and all patients diagnosed with HBV associated HCC between 2008 and 2012 (HBV-HCC group) were enrolled in the present study. Clinical features, BMI, lipid profiles, presence of diabetes mellitus, hypertension, and metabolic syndrome were compared between the two groups. RESULTS: Cryptogenic HCC group was composed of 35 patients (19 males and 16 females) with a mean age of 70+/-11 years. HBV-HCC group was composed of 406 patients (318 males and 88 females) with a mean age of 56+/-7 years. Patients in the cryptogenic HCC group were older (p=0.001) and female dominant (p=0.042) than those in the HBV-HCC group. There were no differences in the laboratory test results including lipid profiles and Child-Turcotte-Pugh class between the two groups. Patients in the cryptogenic HCC group had higher prevalence of diabetes (37% vs. 17%, p=0.015), hypertension (49% vs. 27%, p=0.051), metabolic syndrome (37% vs. 16%, p=0.001), and higher BMI (25.3 kg/m2 vs. 24.1 kg/m2, p=0.042) than those in the HBV-HCC group. The tumor stage was more advanced (stage III and IV) at diagnosis in the cryptogenic HCC group than in the HBV-HCC group (60% vs. 37%, p=0.007). CONCLUSIONS: Cryptogenic HCC has clinical features similar to that of NAFLD and is diagnosed at a more advanced tumor stage.
Age Factors ; Aged ; Body Mass Index ; Carcinoma, Hepatocellular/*diagnosis/etiology/pathology ; Diabetes Complications ; Diabetes Mellitus/pathology ; Female ; Hepatitis B/complications ; Humans ; Hypertension/complications ; Lipids/blood ; Liver Neoplasms/*diagnosis/etiology/pathology ; Male ; Metabolic Syndrome X/complications ; Middle Aged ; Neoplasm Staging ; Non-alcoholic Fatty Liver Disease/*diagnosis/pathology ; Risk Factors ; Severity of Illness Index ; Sex Factors

BACKGROUNDPatients with atherosclerotic renal artery stenosis (ARAS) are in substantial risk of cardiovascular adverse events. We investigated whether myocardial infarction patients with ARAS are in additional risk of cardiovascular events.

METHODSIn this retrospective study, 257 patients with type 1 myocardial infarction were enrolled. Median follow-up was 42 months. Composite endpoint events are analyzed by definitions of ARAS as ≥ 50% or ≥ 70% diameter stenosis.

RESULTSDefining ARAS as ≥ 70% diameter stenosis, ARAS was a significant predictor for composite endpoint events including death, non-fatal myocardial infarction, ischaemic stroke and intracranial haemorrhage, rehospitalisation for cardiac failure (HR: 4.381; 95% CI: 1.770-10.842) by Cox regression analysis, but not for death. Diabetes mellitus was also a significant predictor for composite endpoint events (HR: 2.756; 95% CI: 1.295-5.863). However, defining ARAS ≥ 50% diameter stenosis, ARAS was no longer a significant predictor for composite endpoint events or death.

CONCLUSIONSAlthough not associated with mortality, ARAS ≥ 70% is associated with major adverse cardiac events after acute myocardial infarction. For prognosis, ≥ 70% diameter stenosis is a more appropriate criteria for ARAS definition than ≥ 50% diameter stenosis.

Atherosclerosis ; pathology ; Cardiovascular Diseases ; etiology ; Diabetes Complications ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Myocardial Infarction ; complications ; Renal Artery Obstruction ; complications ; pathology ; Retrospective Studies

In covering wounds, efforts should include utilization of the safest and least invasive methods with goals of achieving optimal functional and cosmetic outcome. The recent development of advanced wound healing technology has triggered the use of cells to improve wound healing conditions. The purpose of this review is to provide information on clinically available cell-based treatment options for healing of acute and chronic wounds. Compared with a variety of conventional methods, such as skin grafts and local flaps, the cell therapy technique is simple, less time-consuming, and reduces the surgical burden for patients in the repair of acute wounds. Cell therapy has also been developed for chronic wound healing. By transplanting cells with an excellent wound healing capacity profile to chronic wounds, in which wound healing cannot be achieved successfully, attempts are made to convert the wound bed into the environment where maximum wound healing can be achieved. Fibroblasts, keratinocytes, adipose-derived stromal vascular fraction cells, bone marrow stem cells, and platelets have been used for wound healing in clinical practice. Some formulations are commercially available. To establish the cell therapy as a standard treatment, however, further research is needed.
Blood Platelets/metabolism ; Cell- and Tissue-Based Therapy ; Diabetes Mellitus, Type 2/complications/pathology ; Fibroblasts/cytology/transplantation ; Humans ; Keratinocytes/cytology/transplantation ; Stromal Cells/cytology/transplantation ; Tissue Engineering ; Ulcer/etiology/therapy ; *Wound Healing

We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-beta1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRalpha, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRalpha and SREBP-1 expression and oxidative stress.
Animals ; Bilirubin/pharmacology/*therapeutic use ; Cell Line, Tumor ; Creatine/blood ; Diabetes Mellitus, Experimental/chemically induced/complications/*pathology ; Diabetic Nephropathies/*drug therapy/etiology ; Disease Models, Animal ; Kidney/pathology ; Lipoproteins, HDL/blood ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NADPH Oxidase/metabolism ; Orphan Nuclear Receptors/antagonists & inhibitors/genetics/metabolism ; Oxidative Stress/drug effects ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Streptozocin/toxicity ; Triglycerides/analysis/*biosynthesis/blood

BACKGROUND/AIMS: The red-blood-cell distribution width (RDW) is a newly recognized risk marker in patients with cardiovascular disease, but its role in nonalcoholic fatty liver disease (NAFLD) has not been well defined. The aim of the present study was to determine the association between RDW values and the level of fibrosis in NAFLD according to BARD and FIB-4 scores. METHODS: This study included 24,547 subjects who had been diagnosed with NAFLD based on abdominal ultrasonography and questionnaires about alcohol consumption. The degree of liver fibrosis was determined according to BARD and FIB-4 scores. The association between RDW values and the degree of fibrosis in NAFLD was analyzed retrospectively. RESULTS: After adjusting for age, hemoglobin level, mean corpuscular volume, history of hypertension, history of diabetes, and high-sensitivity C-reactive protein, the RDW values were 12.61+/-0.41% (mean+/-SD), 12.70+/-0.70%, 12.77+/-0.62%, 12.87+/-0.82%, and 13.25+/-0.90% for those with BARD scores of 0, 1, 2, 3, and 4, respectively, and 12.71+/-0.72%, 12.79+/-0.66%, and 13.23+/-1.52% for those with FIB-4 scores of <1.30, 1.31-2.66, and > or =2.67, respectively (P<0.05). The prevalence of advanced fibrosis (BARD score of 24 and FIB-4 score of > or =1.3) increased with the RDW [BARD score: 51.1% in quartile 1 (Q1) vs. 63.6% in Q4; FIB-4 score: 6.9% in Q1 vs. 10.5% in Q4; P<0.001]. After adjustments, the odds ratio of having advanced fibrosis for those in Q4 compared to Q1 were 1.76 (95%CI=1.55-2.00, P<0.001) relative to BARD score and 1.69 (95%CI=1.52-1.98, P<0.001) relative to FIB-4 score. CONCLUSIONS: Elevated RDW is independently associated with advanced fibrosis in NAFLD.
Adult ; Alcohol Drinking ; C-Reactive Protein/analysis ; Diabetes Mellitus/pathology ; Erythrocyte Indices ; Fatty Liver/complications/*diagnosis/ultrasonography ; Female ; Humans ; Hypertension/pathology ; Liver Cirrhosis/*diagnosis/epidemiology/etiology ; Male ; Middle Aged ; Odds Ratio ; Prevalence ; Questionnaires ; Severity of Illness Index

Aged ; Diabetes Mellitus, Type 2 ; complications ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prostate-Specific Antigen ; blood ; Prostatic Neoplasms ; blood ; etiology ; pathology ; Retrospective Studies

This cross-sectional study was done to identify and determine the socio-demographic and health-related factors associated with diabetic retinopathy and nephropathy screening in Korea. Participants included 2,660 adults, aged 40 or older, with diabetes. Of the 2,660 adults, 998 (37%) and 1,226 (46.1%) had received a diabetic retinopathy and a nephropathy screening within one year, respectively. Regarding retinopathy, subjects older than 65, living in urban areas, with high educational levels, and with self-reported "unhealthy" status were likely to receive annual screening. Subjects living in urban areas, with higher educational levels, with self-reported "fair" or "unhealthy" status, and with 1 to 2 co-morbidities were likely to receive annual nephropathy screening. The Korea Composite Stock Price Index (KOSPI) continued to rise until 2007 when it started to decline over the subsequent years, following the same curve as the diabetic retinopathy and nephropathy screening rates during that time. Together with the financial matter, lack of patient education proved to be a hindrance to diabetes-related screening. The relatively low screening rates in Korea compared to the Western countries are likely to be due to the difference in the health system, economic situations and national demographics.
Adult ; Aged ; Cross-Sectional Studies ; Diabetes Complications/pathology ; Diabetes Mellitus/diagnosis ; Diabetic Nephropathies/diagnosis/*etiology ; Diabetic Retinopathy/diagnosis/*etiology ; Female ; Health Behavior ; Health Status ; Humans ; Male ; Mass Screening ; Middle Aged ; Nutrition Surveys ; Odds Ratio ; Republic of Korea ; Risk Factors ; Severity of Illness Index