Association of plasminogen activator inhibitor-1 and fibroblastic growth factor 21 in 3 groups of type 2 diabetes: Without overweight/obesity, free of insulin resistance, and without hepatosteatosis.

The physiological effects of fibroblast growth factor 21 (FGF21), leading to beneficial metabolic outcomes, have been extensively revealed in recent decades. Significantly elevated serum levels of FGF21 in obesity and type 2 diabetes mellitus (T2DM) are referred to as FGF21 resistance. However, Asian population tend to develop metabolic disorders at a lesser degree of obesity than those of Western. This study aimed to explore factors potentially related to serum FGF21 according to the severity of metabolic disorders in patients with T2DM. This cross-sectional study included 176 T2DM patients. The patients were categorized according to whether they had hepatic steatosis (fatty liver index [FLI] ≥ 60), insulin resistance (homeostasis model assessment of insulin resistance [HOMA-R] ≥ median), and/or overweight/obesity (body mass index [BMI] ≥ 25.0 kg/m2). Independent predictors of serum FGF21 were determined using multiple linear regression analysis in these 3 groups of T2DM patients. Circulating FGF21 levels were correlated positively with BMI, abdominal fat areas, leptin, and plasminogen activator inhibitor-1 (PAI-1). After adjustment for potential confounders, multiple linear regression analysis identified leptin as a factor strongly associated with serum FGF21 levels in all patients. Moreover, PAI-1 was a significant predictor of FGF21 in those with FLI < 60, BMI < 25.0 kg/m2, and HOMA-R < median, while leptin was the only independent factor in each of their counterparts. The factors related to serum FGF21 differ according to the severity of metabolic disorders. FGF21 appears to be independently associated with PAI-1 in T2DM patients: without overweight/obesity, those free of insulin resistance, and those without hepatic steatosis.

Adiponectin Paradox More Evident in Non-Obese Than in Obese Patients with Diabetic Microvascular Complications.

Aims/Introduction: Adiponectin is generally regarded as a beneficial molecule, protecting against insulin resistance and atherosclerosis, and its serum levels are low in individuals with obesity as well as in those with type 2 diabetes (T2DM). However, several clinical studies have shown associations between high adiponectin values and major health concerns. These conflicting findings are termed the "adiponectin paradox". Similarly, these paradoxical adiponectin elevations were observed in patients with diabetic microvascular complications. This cross-sectional study aimed to identify differences in factors, including adiponectin, related to diabetic vascular complications between non-obese and obese patients. Materials and Methods: Study patients with T2DM were non-obese (n=197) or obese (n=197), matched by a propensity score model adjusted with age and gender. Independent factors for each of the microvascular complications were determined using multivariate logistic regression analyses. Results: The prevalence of nephropathy was high in obese T2DM patients. In addition to long diabetes duration, elevated adiponectin was a common characteristic of patients with microvascular complications. Logistic regression analyses for microvascular complications revealed adiponectin to be highly related to retinopathy (odds ratio [OR], 1.138; 95%confidence intervals [CI], 1.004-1.289, p<0.001), nephropathy (OR, 1.192; CI, 1.077-1.319, p<0.001) and neuropathy (OR, 1.217; CI, 1.071-1.384, p<0.001), in non-obese patients. In contrast, the association between adiponectin values and complications was modest in obese patients. Conclusion: Adiponectin regulation in response to vascular damage differed between non-obese and obese patients, suggesting that adiponectin regulation is compromised by fat accumulation. Assuming that paradoxical elevation of adiponectin in vascular damage is a compensatory response, we speculate that responsive upregulation might be insufficient in obese patients. These newly-recognized differences in adiponectin values might lead to novel insights into adiponectin regulation and our understanding of the adiponectin paradox.

Evaluation of High Intracranial Plaque Prevalence in Type 2 Diabetes Using Vessel Wall Imaging on 7 T Magnetic Resonance Imaging.

BACKGROUND: While type 2 diabetes (T2D) is a major risk for ischemic stroke, the associated vessel wall characteristics remain essentially unknown. This study aimed to clarify intracranial vascular changes on three-dimensional vessel wall imaging (3D-VWI) using fast spin echo by employing 7Tesla (7T) magnetic resonance imaging (MRI) in T2D patients without advanced atherosclerosis as compared to healthy controls. METHODS: In 48 T2D patients and 35 healthy controls, the prevalence of cerebral small vessel diseases and intracranial plaques were evaluated by 3D-VWI with 7T MRI. RESULTS: The prevalence rate of lacunar infarction was significantly higher in T2D than in controls (n = 8 in T2D vs. n = 0 in control, p = 0.011). The mean number of intracranial plaques in both anterior and posterior circulation of each subject was significantly larger in T2D than in controls (2.23 in T2D vs. 0.94 in control, p < 0.01). In T2D patients, gender was associated with the presence of intracranial plaques. CONCLUSION: This is the first study to demonstrate the high prevalence of intracranial plaque in T2D patients with neither confirmed atherosclerotic disease nor symptoms by performing intracranial 3D-VWI employing 7TMRI. Investigation of intracranial VWI with 7T MRI is expected to provide novel insights allowing early intensive risk management for prevention of ischemic stroke in T2D patients.

The Effects of Imeglimin on the Daily Glycemic Profile Evaluated by Intermittently Scanned Continuous Glucose Monitoring: Retrospective, Single-Center, Observational Study.

INTRODUCTION: Imeglimin is a novel antidiabetic drug that amplifies glucose-stimulated insulin secretion (GSIS) and improves insulin sensitivity. Several randomized clinical studies have shown the efficacy of imeglimin for glycemic control in patients with type 2 diabetes (T2D). We aimed to evaluate the short-term effects and safety of imeglimin in terms of glycemic control, as assessed by intermittently scanned continuous glucose monitoring (isCGM). METHODS: This retrospective and observational study of 32 patients who were administered imeglimin in addition to existing treatment regimens was designed to evaluate glycemic profiles. The patients were monitored for more than 4 weeks, including the day of starting imeglimin. The changes in glycemic indices, including mean glucose level, coefficient of variation (CV), time in range (TIR) and time above range (TAR), before and after imeglimin administration were analyzed, and data on adverse effects were collected by interview. RESULTS: Imeglimin administration significantly improved the mean values of glucose (from 159.0 ± 27.5 mg/dL to 141.7 ± 22.1 mg/dL; p < 0.001), TIR (from 67.9 ± 17.0% to 79.5 ± 13.3%; p < 0.001) and TAR (from 29.4 ± 17.5% to 17.9 ± 13.7%; p < 0.001) and tended to improve CV (from 29.0 ± 6.1 to 27.4 ± 5.58; p = 0.058). The curves of 24-h mean glucose level for all 32 subjects were shifted downward from the baseline after imeglimin administration. The high mean glucose level, high TAR, low TIR, low body mass index and low C-peptide were related to the efficacy of imeglimin for glycemic control. The main adverse effects were gastrointestinal disorders, and the incidence of hypoglycemia was increased in cases receiving a combination of imeglimin plus insulin or a glinide agent. CONCLUSION: Imeglimin clearly shifted the daily glucose profile into an appropriate range in Japanese T2D patients, indicating improvement of short-term glycemic control. Imeglimin is thought to be a promising therapeutic agent for T2D patients, especially those with a low insulin secretory capacity, which is a common phenotype in East-Asian subjects with glucose intolerance.

Weight Gain After 20 Years of Age is Associated with Unfavorable Lifestyle and Increased Prevalence of Metabolic Disorders.

PURPOSE: It is unclear what kind of modifiable lifestyle factors are associated with long-time weight gain in adulthood. To clarify the lifestyle behavior related to body weight gain since the age of 20 years, we explored the lifestyle risk factor, independently associated with excessive weight gain after 20 years of age as compared to those in subjects with a stable weight, with matching of age, gender, and the current body mass index (BMI). PATIENTS AND METHODS: From baseline data of a general population-based cohort study, we designed a cross-sectional analysis collecting individual data of medical health check-ups and a questionnaire related to lifestyle, including amount of sleep, frequency of eating breakfast, average times per day engaged in walking and sitting in the prior year, and smoking habits. These data were compared between the subjects with weight gain ≥10kg (n=3601) and <10kg (n=3601) after age 20, matched by a propensity score model which included current BMI, age and gender. We used multivariable logistic regressions to assess the lifestyle factor's association with high weight gain. RESULTS: Participants who gained ≥10 kg were significantly more likely to sleep <5 hours or ≥9 hours per night, skip breakfast, engage in walking <1 hour per day, and sit ≥5 hours per day than those who gained <10kg. Multivariable logistic regressions analyses showed that, with adjusting for potential confounder, the lifestyles with the positive association with high weight gain were skipping breakfast (OR 1.252; 95% CI 1.053-1.489, vs regularly), long sleeping duration (9 hours/day≤ OR 1.613; 95% CI 1.018-2.557 vs 5≤-<7 hours/day), and former smoker (OR 1.163; 95% CI 1.008-1.343 vs never smoker), while walking duration was negatively associated with high weight gain. Furthermore, despite similar current BMI, participants with weight gain ≥10kg had significantly higher values for waist circumference, blood pressure, HbA1c, LDL-C, triglycerides, and hepatic enzyme levels than those with weight gain <10kg. Similarly, the prevalence rates of hypertension, dyslipidemia, metabolic syndrome (MetS), and former smoker were higher in the participants with weight gain ≥10kg. CONCLUSION: Major weight gain after 20 years of age was associated with unfavorable lifestyle factors and greater waist circumference, possibly leading to elevated risk for MetS and other non-communicable diseases. These findings highlight the importance of maintaining both weight at age 20 and a favorable lifestyle throughout adulthood.

Serum C-X-C motif chemokine ligand 14 levels are associated with serum C-peptide and fatty liver index in type 2 diabetes mellitus patients.

AIMS/INTRODUCTION: Recent studies have suggested C-X-C motif chemokine ligand 14 (CXCL14), secreted from adipose tissue, to play an important role in the pathogenesis of metabolic syndrome. However, the clinical significance of CXCL14 in humans has not been elucidated. This study aimed to assess correlations between serum CXCL14 levels and clinical parameters in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: In total, 176 individuals with type 2 diabetes mellitus were recruited. Serum CXCL14 concentrations were determined by enzyme-linked immunosorbent assay. We examined the associations of serum CXCL14 levels with laboratory values, abdominal computed tomography image information, surrogate markers used for evaluating the pathological states of diabetes, obesity and atherosclerosis. RESULTS: Serum CXCL14 levels correlated positively with body mass index, waist circumference, subcutaneous and visceral fat areas, and serum alanine transaminase, uric acid, total cholesterol, low-density lipoprotein cholesterol, triglycerides and C-peptide (CPR) levels. In contrast, CXCL14 levels correlated inversely with age, pulse wave velocity and serum adiponectin levels. Multiple linear regression analysis showed serum levels of CPR (ß = 0.227, P = 0.038) and the fatty liver index (ß = 0.205, P = 0.049) to be the only parameters showing independent statistically significant associations with serum CXCL14 levels. CONCLUSIONS: Serum CXCL14 levels were independently associated with serum CPR and fatty liver index in patients with type 2 diabetes mellitus. In these patients, a high serum CPR concentration might reflect insulin resistance rather than ß-cell function, because CXCL14 showed simple correlations with obesity-related parameters. Collectively, these data suggested that serum CXCL14 levels in type 2 diabetes patients might be useful predictors of elevated serum CPR and hepatic steatosis.

Association of epicardial adipose tissue with serum level of cystatin C in type 2 diabetes.

OBJECTIVE: Accumulation of epicardial adipose tissue (EAT) is considered to be a cardiovascular risk factor independent from visceral adiposity, obesity, hypertension and diabetes. We explored the parameters related to EAT accumulation, aiming to clarify the novel pathophysiological roles of EAT in subjects with type 2 diabetes (T2DM). METHODS: We examined the laboratory values, including cystatinC, and surrogate markers used for evaluating atherosclerosis. EAT was measured as the sum of the adipose tissue area, obtained by plain computed tomography scans in 208 subjects with T2DM but no history of coronary artery disease. RESULTS: EAT correlated positively with age, body mass index (BMI), visceral fat area, leptin, cystatin C and C-peptide, while correlating negatively with adiponectin, estimated glomerular filteration rate (eGFR) and the liver-to-spleen ratio. Multiple linear regression analysis revealed serum cystatin C (ß = 0.175), leptin (ß = 0.536), BMI (ß = 0.393) and age (ß = 0.269) to be the only parameters showing independent statistically significant associations with EAT. When cystatin C was replaced with eGFR, eGFR showed no significant correlation with EAT. In reverse analysis, serum cystatin C was significantly associated with EAT after adjustment in multivariate analysis. DISCUSSION: EAT accumulation and elevated cystatin C have been independently regarded as risk factors influencing atherosclerosis. The strong association between EAT and cystatin C demonstrated herein indicates that EAT accumulation may play an important role in Cystatin C secretion, possibly contributing to cardiometabolic risk in T2DM patients.

Association of Advanced Glycation End Products with coronary Artery Calcification in Japanese Subjects with Type 2 Diabetes as Assessed by Skin Autofluorescence.

AIM: Advanced glycation end products (AGE) are considered to be among the critical pathogenic factors involved in the progression of diabetic complications. Skin autofluorescence (AF), a noninvasive measurement of AGE accumulation, has been recognized as a useful and convenient marker for diabetic vascular diseases in Caucasians. This study aimed to evaluate the association of tissue AGE, assessed using skin AF, with coronary artery calcification in Japanese subjects with type 2 diabetes. METHODS: In total, 122 Japanese subjects with type 2 diabetes enrolled in this cross-sectional study underwent multi-slice computed tomography for total coronary artery calcium scores (CACS) estimation and examination with a skin AF reader. RESULTS: Skin AF positively correlated with age, sex, diabetes duration, pulse wave velocity, systolic blood pressure, serum creatinine, and CACS. In addition, skin AF results negatively correlated with BMI, eGFR, and serum C-peptide concentration. According to multivariate analysis, age and systolic blood pressure showed strong positive correlation and eGFR showed negative correlation with skin AF values. Multiple linear regression analyses revealed a significant positive correlation between skin AF values and logCACS, independent of age, sex, diabetes duration, HbA1c, BMI, IMT, and blood pressure. However, skin AF showed no association with serum levels of AGE, such as Nε-(carboxymethyl) lysine and 3-deoxyglucosone. CONCLUSION: Skin AF results positively correlated with CACS in Japanese subjects with type 2 diabetes. This result indicates that AGE plays a role in the pathogenesis of diabetic macrovascular disease. Measurement of skin AF values may be useful for assessing the severity of diabetic complications in Japanese subjects.

Non-Islet Cell Tumor Hypoglycemia Is Caused by Big IGF-II in a Patient with a Carcinosarcoma of the Uterus.

We report a 72-year-old Japanese woman with severe hypoglycemia. The laboratory data, which revealed the suppression of serum insulin, suggested the existence of non-islet cell tumor hypoglycemia (NICTH). Abdominal computed tomography demonstrated the presence of a huge uterine tumor. The patient was treated with a continuous infusion of glucose, but died of sepsis on day 46. An autopsy revealed the pathological diagnosis to be a carcinosarcoma of the uterus. Interestingly, an immunohistochemical study discovered the expression of insulin-like growth factor (IGF)-II in both the carcinoma and sarcoma cells. In addition, an immunoblot analysis of blood samples revealed the presence of circulating big IGF-II. Therefore, this is a novel case of NICTH that was caused by a uterine carcinosarcoma.

Response to the dipeptidyl peptidase-4 inhibitors in Japanese patients with type 2 diabetes might be associated with a diplotype of two single nucleotide polymorphisms on the interleukin-6 promoter region under a certain level of physical activity.

AIMS/INTRODUCTION: Muscle-derived interleukin-6 (IL-6) has been reported to promote glucagon-like peptide-1 (GLP-1) secretion, and we explored the association of single nucleotide polymorphisms (SNPs) in the human IL-6 promoter region with the responsiveness to dipeptidyl peptidase-4 inhibitors (DPP-4Is), drugs that increase circulating GLP-1. MATERIALS AND METHODS: The present observational study enrolled Japanese patients with type 2 diabetes who took a DPP-4I over 3 months, and most of the clinical information was collected retrospectively. We defined non-responders as those having less than a 0.2% decrease of the glycated hemoglobin level at 3 or 4 months after starting DPP-4I treatment. Physical activity was retrospectively estimated by the Japanese short version of International Physical Activity Questionnaire. RESULTS: We studied 316 patients whose physical activity corresponding to the season of the DPP-4I administration was estimated. The non-responder rate was 29.7%. We analyzed rs1800796 and rs2097677, both are suggested to be functional in Japanese. Multivariate analysis for all patients showed that the adjusted odds ratio for the non-responder risk of the diplotype rs1800796 G/*-rs2097677 A/* against C/C-G/G (OR_G*A*) was 0.445 (P = 0.068). When patients were stratified by the International Physical Activity Questionnaire into low (n = 149) and moderate/high (n = 167) activity groups, however, OR_G*A* in each group was 1.58 (P = 0.615) and 0.153 (P = 0.003), respectively. CONCLUSIONS: The diplotype rs1800796 G/*-rs2097677 A/* might contribute to responsiveness to DPP-4Is in Japanese patients with type 2 diabetes under a certain level of physical activity. However, further investigation is warranted to confirm this.

Association of coronary artery calcification with MDA-LDL-C/LDL-C and urinary 8-isoprostane in Japanese patients with type 2 diabetes.

OBJECTIVE: Oxidative stress has been implicated in the development of coronary artery calcification (CAC). However, there are few reports on this issue in Japanese patients with diabetes. In this study, we examined the association of the CAC score (CACS) with oxidative stress markers. METHODS: The study subjects were 163 Japanese patients with type 2 diabetes (75 men and 88 women). The CACS (Agatston unit: AU) was measured by multi-detector computed tomography (MDCT), and the oxidative stress markers, such as the urinary 8-isoprostane and 8-hydroxydeoxyguanosine (8-OHdG) and serum malondialdehyde (MDA)-LDL cholesterol were measured. The relationships between CACS and oxidative stress markers were statistically analyzed. RESULTS: Compared with the CACS 0-400 AU group (n=132), the age, duration of diabetes, urinary 8-isoprostane levels, serum MDA-LDL-C/LDL-C and maximum intima media thickness (IMT) were higher, and body mass index and HbA1c level were lower, in the CACS >400 AU group (n=31). The multiple logistic regression analysis showed that a CAC >400 AU was independently associated with the urinary 8-isoprostane (>median) (OR=2.54, 95% CI=1.03-6.32, p=0.044), MDA-LDL-C/LDL-C (>median) (OR=2.62, 95% CI=1.07-6.40, p=0.035) and HbA1c (>median) (OR=0.32, CI=0.12-0.87, p<0.025). Focusing on oxidative stress, a higher MDA-LDL-C/LDL-C (p=0.026) and a higher urinary 8-isoprostane level (p=0.074) were associated with the CACS. CONCLUSION: The CACS was found to be independently associated with the MDA-LDL-C/LDL-C and urinary 8-isoprostane levels in Japanese patients with type 2 diabetes.

Different susceptibility to insulin resistance and fatty liver depending on the combination of TNF-α C-857T and adiponectin G+276T gene polymorphisms in Japanese subjects with type 2 diabetes.

The C-857T promoter polymorphism of TNF-α gene is associated with obese type 2 diabetes, while the adiponectin G+276T gene polymorphism in intron 2 may influence the fat accumulation in the liver. In this study, we examined effects of these polymorphisms on clinical markers of insulin resistance and fatty liver (a liver/spleen CT ratio < 0.9). These polymorphisms were determined in 342 Japanese subjects with type 2 diabetes. The liver/spleen CT ratio was lower in the subjects with the adiponectin +276G/G genotype than that in the subjects with the +276T allele (P < 0.05), indicating that fat accumulation in the liver is associated with the +276G/G genotype. Multiple comparisons among the 4 combinations of each polymorphism of the TNF-α and adiponectin genes revealed a significant difference in the liver/spleen CT ratio (P < 0.05) among the 4 groups, indicating that the gene combinations influence the degree of fat accumulation in the liver. The subjects carrying the TNF-α -857T allele (C/T or T/T genotype) and the adiponectin +276G/G genotype had greater risks for fatty liver and insulin resistance that was evaluated by higher levels of fasting insulin and homeostasis model assessment of insulin resistance, as compared with the other groups. Therefore, Japanese subjects with the TNF-α -857T allele and the adiponectin +276G/G genotype may be more susceptible to insulin resistance and fatty liver. The present study provides the evidence for the interaction between TNF-α and adiponectin genes in the insulin resistance and fatty liver in Japanese subjects with type 2 diabetes.

Serum CXCL1 concentrations are elevated in type 1 diabetes mellitus, possibly reflecting activity of anti-islet autoimmune activity.

BACKGROUND: Identification of unique inflammatory markers may facilitate prediction of type 1 diabetes mellitus (T1DM). We previously compared transcript profiles of bone marrow-derived dendritic cells from non-obese diabetic mice with those from non-obese non-diabetic mice and found that bone marrow-derived dendritic cells' expressions of inflammatory mediators, including chemokine (C-X-C motif) ligand 1 (CXCL1), were three to five times higher in 4-week-old female non-obese diabetic mice than in non-obese non-diabetic mice. In humans, microarray analysis results have suggested this chemokine be a biomarker representing active anti-islet autoimmunity. We investigated whether serum CXCL1 levels, reflecting active autoimmune processes, might serve as biomarkers for T1DM. METHODS: The study groups consisted of 26 subjects with acute-onset T1DM, 20 with slowly progressive T1DM, and 20 with type 2 diabetes mellitus as disease controls. All subjects were Japanese. CXCL1 in sera were quantified by solid phase enzyme-linked immunosorbent assays. RESULTS: Serum CXCL1 levels were significantly higher in subjects with acute-onset [median 113.2 ng/mL (41.75-457.2)] or slowly progressive [median 100.8 ng/mL (32.87-225.0)] T1DM than in those with type 2 diabetes mellitus [median 71.58 ng/mL (32.45-152.6), p=0.01 and 0.03, respectively, Mann-Whitney U-test]. Decreases in fasting C-peptide levels per year correlated significantly with CXCL1 levels (n=11, r2=0.524, p=0.012) in a subpopulation of slowly progressive T1DM subjects displaying preserved beta-cell function. CONCLUSIONS: To our knowledge, this is the first study to show elevated serum CXCL1 in T1DM subjects, regardless of diabetes subtype, as compared to control type 2 diabetes mellitus subjects. We propose serum CXCL1 elevation to be a good T1DM marker, possibly indicating a predisposition to autoimmune disease development.

Recurrent hypoglycemia during pregnancies in a woman with multiple autoantibodies including anti-insulin receptor antibody and anti-platelet antibody, whose serum lowered murine blood glucose levels and phosphorylated insulin receptor of CHO-IR cells.

We report a rare case of recurrent hypoglycemia in a pregnant woman during the period of pregnancies. She suffered from severe hypoglycemia and intrauterine fetal death during the first pregnancy. Thereafter, there was no hypoglycemia, and no obvious cause of hypoglycemia was found by close examinations. Two years later, at eight weeks into the second pregnancy, hypoglycemia recurred. The patient had multiple auto-antibodies including anti-insulin receptor antibody and anti-platelet antibody associated with decreased platelet count. She completed the pregnancy with continuous intravenous administration of glucose that prevented hypoglycemia and finally delivered a healthy baby by Caesarian section. Both the hypoglycemia and thrombocytopenia, and the auto-antibodies disappeared after the delivery. We analyzed the patient's serum as a possible cause of hypoglycemia. Administration of the serum lowered blood glucose levels of mice more strongly than control serum. In addition, the serum phosphorylated tyrosine of insulin receptor of Chinese hamster ovary cells overexpressing human insulin receptors (CHO-IR cells) in vitro. These results suggest that multiple auto-antibodies might have been induced by a trigger of pregnancy, although the precise mechanism was unclear, and the anti-insulin receptor antibody and anti-platelet antibody might have induced hypoglycemia and thrombocytopenia, respectively, during the pregnancy.

Analysis of cell cycle-related proteins in gastric intramucosal differentiated-type cancers based on mucin phenotypes: a novel hypothesis of early gastric carcinogenesis based on mucin phenotype.

BACKGROUND: Abnormalities of cell cycle regulators are common features in human cancers, and several of these factors are associated with the early development of gastric cancers. However, recent studies have shown that gastric cancer tumorigenesis was characterized by mucin expression. Thus, expression patterns of cell cycle-related proteins were investigated in the early phase of differentiated-type gastric cancers to ascertain any mechanistic relationships with mucin phenotypes. METHODS: Immunostaining for Cyclins D1, A, E, and p21, p27, p53 and beta-catenin was used to examine impairments of the cell cycle in 190 gastric intramucosal differentiated-type cancers. Mucin phenotypes were determined by the expressions of MUC5AC, MUC6, MUC2 and CD10. A Ki-67 positive rate (PR) was also examined. RESULTS: Overexpressions of p53, cyclin D1 and cyclin A were significantly more frequent in a gastric phenotype than an intestinal phenotype. Cyclin A was overexpressed in a mixed phenotype compared with an intestinal phenotype, while p27 overexpression was more frequent in an intestinal phenotype than in a mixed phenotype. Reduction of p21 was a common feature of the gastric intramucosal differentiated-type cancers examined. CONCLUSIONS: Our results suggest that the levels of some cell cycle regulators appear to be associated with mucin phenotypes of early gastric differentiated-type cancers.

Association of the TNF-{alpha}-C-857T polymorphism with resistance to the cholesterol-lowering effect of HMG-CoA reductase inhibitors in type 2 diabetic subjects.

OBJECTIVE An association of the C-857T polymorphism of the tumor necrosis factor-alpha (TNF-alpha) gene promoter region with LDL cholesterol levels has been reported. This study was designed to evaluate the relationship between the TNF-alpha-C-857T polymorphism and LDL cholesterol levels according to statin treatment in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS DNA was obtained from 322 Japanese subjects (160 male and 162 female) with type 2 diabetes, and TNF-alpha-C-857T polymorphisms were determined by direct sequencing. Serum LDL cholesterol was measured by a direct method. RESULTS Although serum LDL cholesterol levels were significantly higher in the T carriers (C/T + T/T) than in the non-T carriers (C/C) (3.14 +/- 0.86 vs. 2.89 +/- 0.75 mmol/l, P < 0.05), there was no difference in LDL cholesterol levels between the non-T carriers and the T carriers in statin-untreated subjects (2.87 +/- 0.73 vs. 2.89 +/- 0.76 mmol/l, NS), whereas in statin-treated subjects, LDL cholesterol levels were significantly higher in the T carriers than in the non-T carriers (3.43 +/- 0.89 vs. 2.90 +/- 0.78 mmol/l, P = 0.0007). There were no differences in HDL cholesterol and triglyceride levels between the non-T carriers and the T carriers in both statin-treated and -untreated subjects. The percent decrease in LDL cholesterol levels after administration of statins was significantly smaller in the T carriers compared with the non-T carriers (27.6 vs. 36.4%, P = 0.031). CONCLUSIONS The mutant allele of the C-857T promoter polymorphism of the TNF-alpha gene may predispose to resistance to the LDL cholesterol-lowering effect of statins and could be one of the markers used to predict the efficacy of statins.

Decrease in mortality rate of chronic obstructive pulmonary disease (COPD) with statin use: a population-based analysis in Japan.

It has been well established that statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, reduce mortality from cardiovascular diseases. Statins, a class of cholesterol-lowering drug, may also affect mortality from various diseases by their pleiotropic effects of anti-inflammatory and anti-oxidative activities. However, there are only few reports concerning the effects of statins on diseases other than cardiovascular diseases. We therefore designed a population-based analysis, using the data from marketing surveys on statin sales and government reports on mortalities. We compared the statin use as expressed by statin sales per capita in the aged (> or = 65-year-old) population with mortality from major causes of death among 47 prefectures in Japan. As expected, there were significant negative correlations between statin sales per capita and mortality from cardiovascular diseases (p < 0.05). In addition, we found that there was a correlation between statin sales and the decrease in mortality from chronic obstructive pulmonary disease (COPD) (p < 0.0001), senility (p < 0.01), pneumonia (p < 0.05), accidents (p < 0.05), or all death causes (p < 0.05). However, statin sales were not associated with mortalities from renal failure, liver diseases, suicide, and malignant diseases. These results suggest a broad spectrum of beneficial effects of statins, including reduction of mortality rate of COPD as well as cardiovascular diseases. It will be worthy to confirm the protective effect of statins on COPD by prospective randomized clinical trials.

Association of TNF-alpha gene promoter C-857T polymorphism with higher serum LDL cholesterol levels and carotid plaque formation in Japanese patients with type 2 diabetes.

Little has been known about the role of tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms in metabolic syndrome and atherosclerosis in type 2 diabetes, although TNF-alpha was reported to be involved in these conditions. We examined the association of TNF-alpha gene promoter polymorphisms, G-238A, G-308A, C-857T, C-863A, and T-1031C, with metabolic syndrome and surrogate markers of atherosclerosis in Japanese patients with type 2 diabetes. DNA was obtained from 162 patients and TNF-alpha gene promoter polymorphisms determined by direct sequencing. Allelic frequency of -238A, -308A, -857T, -863A, and -1031C was 0.6%, 2.2%, 11.1%, 16.7%, and 15.7%, respectively. Association of the gene polymorphisms with a number of variables, because of their high frequency, was analyzed in the latter 3 polymorphisms. There were no significant differences in components of metabolic syndrome and variables affecting atherosclerosis, except in case of serum low-density-lipoprotein cholesterol (LDL-C) (111+/-33 vs 125+/-39 mg/dl, p<0.05) between -857C/C and -857(C/T+T/T). In contrast, no significant differences were found in these markers between -863C/C and -863(C/A+A/A) and between -1031T/T and -1031(T/C+C/C). Furthermore, 87% of the patients with -857(C/T+T/T) and 64% with -857C/C had carotid plaques (p<0.05). There was no difference in proportion of patients treated with medications such as statins, fibrates, oral hypoglycemic agents, insulin, or antihypertensive drugs between -857C/C and -857(C/T+T/T). These data imply that TNF-alpha gene polymorphism (C-857T) is likely associated with higher serum LDL-C levels and carotid plaque formation in Japanese patients with type 2 diabetes.

Liver fat content measured by magnetic resonance spectroscopy at 3.0 tesla independently correlates with plasminogen activator inhibitor-1 and body mass index in type 2 diabetic subjects.

We measured liver fat content by 3-Tesla magnetic resonance spectroscopy (MRS) in 34 non- to mild obese Japanese subjects with type 2 diabetes, who were not complicated with any liver diseases including clinical fatty liver (liver/spleen ratio of computed tomography [CT] < 0.9) and were not being treated with oral hypoglycemic agents, insulin, or lipid-lowering agents, and analyzed the relationship between liver fat content and body composition and plasma metabolite. The liver fat content is significantly correlated with variables relating to obesity (body mass index [BMI], body weight, fat mass, waist to hip ratio, visceral fat area, subcutaneous fat area, and serum triglyceride), insulin resistance (fasting plasma insulin and homeostasis model assessment of insulin resistance [HOMA-IR]), adipocytokines (serum plasminogen activator inhibitor-1 [PAI-1] and leptin), and serum cholinesterase, but not CT liver/spleen ratio, which is correlated only with fasting plasma glucose, BMI, and HOMA-IR. Multiple regression analysis revealed that the liver fat content is independently associated with serum PAI-1 level (p < 0.001) and BMI (p < 0.05), but not visceral fat area. MRS is a more sensitive method for quantifying liver fat content than CT in type 2 diabetic subjects with non- to mild obesity and without clinical fatty liver.

Low incidence of vascular complications in patients with diabetes mellitus associated with liver cirrhosis as compared with type 2 diabetes mellitus.

We compared clinical features and vascular complications of patients with diabetes mellitus associated with liver cirrhosis versus patients with type 2 diabetes mellitus. Subjects were 19 patients (LC-DM group) in whom diabetes was diagnosed after development of liver cirrhosis. Control consisted of 38 patients with type 2 diabetes (T2DM group) matched for sex, age, duration of diabetes, body mass index, treatment, and degree of glycemic control, which was determined by glycoalbumin. The LC-DM group had significantly more smokers, higher serum insulin levels, more insulin resistance calculated by homeostasis model assessment, lower blood counts (white and red blood cells, hemoglobin, and platelets), and lower serum levels of total cholesterol, triglyceride, low density lipoprotein cholesterol and lipoprotein (Lp)(a) than the T2DM group. The incidence of diabetic retinopathy and cerebrovascular disease was significantly lower in the LC-DM group compared to the T2DM group. Logistic regression analysis indicated that Lp(a) and the diabetes duration were significant predictors for the retinopathy, while Lp(a) was a significant predictor for the cerebrovascular complication. In diabetes associated with liver cirrhosis, the incidence of diabetic retinopathy and cerebrovascular disease is lower than in type 2 diabetes mellitus in this study, probably because of lower levels of serum Lp(a).