α-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness.

PURPOSE: We aimed to test whether α-internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). PATIENTS AND METHODS: Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation of α-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated α-internexin expression with clinicopathological characteristics. RESULTS: α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin was significantly associated with advanced stage (P < .0001), metastases (P < .0001), and recurrence (P = .003). α-Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P < .0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of α-internexin promoter (-149 to +96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). CONCLUSION: α-Internexin can be a useful prognostic biomarker for PNETs.

Effects of variation in retinol binding protein 4 gene and adipose specific expression of gestational diabetes in Beijing, China.

OBJECTIVE: To investigate the clinical features of GDM in China and the effects of RBP4 genetic variants, and also to identify RBP4 expression changes in mRNA and protein levels. RESEARCH DESIGN AND METHODS: 1595 Chinese pregnant women were included in this study. Four known RBP4 single nucleotide polymorphisms (SNPs) were genotyped in 505 cases and 687 controls. Expression levels of adipose specific RBP4 mRNA and protein were detected in 41 samples of subcutaneous adipose tissue. RESULTS: The estimated indices of insulin resistance were gradually increased from NGT, GIGT to GDM. Two single SNPs were associated with GDM (rs3758539 G vs A, OR=1.446, P=0.009; rs3758539 GG vs AG+AA, OR=1.532, P=0.006; rs12265684C vs G, OR=1.296, P=0.038) and a haplotype of 3 common SNPs [G-G-T] was increased in subjects with GDM and GIGT (OR=1.322, 95% CI 1.054-1.659, P=0.016). RBP4 mRNA expression in adipose tissue of GDM patients was significantly increased in comparison to control subjects (1.438 ± 0.187 vs 1.034 ± 0.062, p=0.025). CONCLUSION: This finding suggests that impaired insulin sensitivity has an early onset in mild gestational intolerance. Two single SNPs were associated with GDM in the case-control study while a haplotype of 3 common SNPs [G-G-T] was increased in glucose intolerance subjects.

[Changes of insulin resistance and islet beta cells function in subjects with high-normal blood pressure].

OBJECTIVE: To investigate the changes of insulin resistance and islet beta cells function in subjects with euglycemia and high-normal blood pressure. METHODS: Total 423 subjects were divided into normal blood pressure group and high-normal blood pressure group. Body height, weight, waist and hip circumference, and biochemical data were measured. Homeostasis model assessment of insulin resistance (HOMA-IR), insulin sensitivity index (ISI)-composite, and first-phase (1 PH) Stumvoll index were calculated. Results Waist circumference, total cholesterol, triglyceride, low-density lipoprotein cholesterol, HOMA-IR were significantly higher and IPH Stumvoll index and ISI-composite were significantly lower in high-normal blood pressure group than in normal blood pressure group (P < 0.05). Systolic blood pressure (SBP) was positively correlated with HOMA-IR (r = 0.122) and negatively correlated with 1PH Stumvoll index (r = -0. 159) and ISI-composite (r = -0.131) (P < 0.05). SBP and triglyceride were independent factors for IPH Stumvoll index. CONCLUSION: Insulin resistance and islet dysfunction may exist in subjects with high-normal blood pressure.

Clinical implications of microsatellite instability and MLH1 gene inactivation in sporadic insulinomas.

CONTEXT: The molecular pathogenesis of sporadic insulinomas is unknown. There is a lack of biomarker to distinguish benign and malignant form of insulinoma. OBJECTIVE: Our objective was to confirm the occurrence of microsatellite instability (MSI) in insulinomas, to identify alterations of mismatch repair (MMR) genes in the tumors, and to evaluate the possibility to distinguish benign and malignant insulinoma or to predict the clinical outcome of patients with these alterations. DESIGN AND PATIENTS: We detected MSI and inactivation of MLH1 gene in 55 sporadic insulinomas by PCR, immunohistochemical staining, allelic typing, analysis of promoter methylation, and exon mutations. Their correlations with clinicopathological characteristics were analyzed with univariate and multivariate statistic analysis. RESULTS: A high rate of MSI (MSI-H) was found in 33% of sporadic insulinomas. Reduced expression of mutL homolog 1 (MLH1) protein was observed in 36% of insulinomas and correlated with MSI-H (P = 0.008). Promoter methylation and loss of heterozygosity of MLH1 gene was found in 31 and 49% of insulinomas, respectively. Reduced expression of MLH1 and MSI-H were significantly associated with both tumor malignancy (P = 0.033 and P = 4.8 x 10(-6), respectively) and incurable disease (P = 0.006 and P = 0.001, respectively). CONCLUSION: High frequency of MSI occurred in sporadic insulinomas. The silencing of MLH1 gene may partially contribute to the MSI-H in the tumors. Assessing MSI-H and expressions of MLH1 could be used to distinguish benign and malignant insulinomas and to predict the outcome of patients.

Association of ghrelin polymorphisms with metabolic syndrome in Han Nationality Chinese.

OBJECTIVE: To investigate the association of ghrelin gene polymorphisms with metabolic syndrome in Han Nationality Chinese. METHODS: A total of 240 patients with metabolic syndrome and 427 adults aged above forty years were recruited. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The allelic frequency of the Leu72Met polymorphism was 17.3% in the patient group and 11.9% in the control group (chi2 = 7.36, P = 0.007). Metabolic syndrome was more prevalent among carriers of the Met72 variant (43.8 vs 33.1%, age- and sex-adjusted odds ratio = 1.57, P = 0.01). No Arg51Gln variants were found in our study subjects. CONCLUSION: Rather than being associated with its individual components, Leu72Met polymorphism is associated with metabolic syndrome in the Han Nationality Chinese. Arg51Gln polymorphism is rare in the Han Nationality Chinese.

Identification of a regulatory single nucleotide polymorphism in the adiponectin (APM1) gene associated with type 2 diabetes in Han nationality.

OBJECTIVE: To identify the genetic defects of the the adiponectin (APM1) gene that contribute to the development of type 2 diabetes (T2DM) and determine the functional single nucleotide polymorphisms (SNPs) in the APM1 gene associated with T2DM in Han nationality. METHODS: The APM1 gene 5'-UTR was screened by direct sequencing to identify common polymorphisms. Identified SNPs were genotyped in 585 nondiabetic controls, 278 subjects with impaired glucose intolerance (IGT) and 212 patients with T2DM. The functions of SNPs in the regulatory region were assessed by reporter gene assay. Possible association between SNPs and plasma APMI levels or metabolic parameters was statistically assessed. RESULTS: Three SNPs were identified in the APM1 gene 5'-UTR. A case-control study revealed that SNP -11377 G/C had significant differences in allele frequencies between T2DM patients and nondiabetic controls (G 0.314/C 0.686 vs. G 0.265/C 0.735, P=0.03). Haplotype analysis of three SNPs in the APM1 gene showed that no significant association of haplotypes with T2DM. IGT was detected in the present study. Reporter gene assay showed that SNP did not influence the transcription efficiency in the 3T3-L1 cell line. CONCLUSION: SNP -11377 G/C in the proximal promoter region of the APM1 gene contributes to the development of T2DM in Han nationality but may not be a functional SNP in the APM1 gene.

[Study on diabetes prevalence in urban China].

OBJECTIVE: To describe the status of diabetic mellitus (DM) prevalence and fast blood glucose level among urban population in China. METHODS: All 16 511 subjects, from households participating in dietary survey, aged over 20 years, were randomly sampled from 44 urban sites in 31 provinces, autonomous regions and municipalities. The diagnosis of DM was based mainly on fast plasma glucose concentration, combining with oral glucose tolerance test and the survey of previous diabetic mellitus diagnosis in local hospitals. RESULTS: The DM prevalence in big cities was 6.13%, 6.08% for male and 6.30% for female. The DM prevalence was 1.07%, 2.72%, 6.50%, 11.62%, 17.36%, 18.32% and 10.06% for 20, 30, 40, 50, 60, 70 and 80 years age groups and the fast plasma glucose levels were (4.74 +/- 0.90) mmol/L, (4.93 +/- 1.03) mmol/L, (5.12 +/- 1.47) mmol/L, (5.42 +/- 1.76) mmol/L, (5.63 +/- 1.88) mmol/L, (5.70 +/- 2. 07) mmol/L, and (5.24 +/- 1.10) mmol/L respectively. The DM prevalence in medium small cities was 3.78%, 3.98% for male and 3.63% for female. The DM prevalence was 0.41%, 1.38%, 3.41%, 9. 4%, 12.56%, 11.23% and 5.56% for 20, 30, 40, 50, 60, 70 and 80 years age groups, and the fast plasma glucose level was (4. 68 +/- 0.58) mmol/L, (4.82 +/- 0.74) mmol/L, (4.99 +/- 1.04) mmol/L, (5.31 +/- 1.55) mmol/L, (5.49 +/- 1.73) mmol/L, (5.39 +/- 1.62) mmol/L, (5.22 +/- 1.30) mmol/L respectively in small and medium cities. CONCLUSION: For DM and fast plasma glucose level, the effects of increasing with the age should be very obvious either in big cities or medium and small cities. The DM prevalence rate in middle aged and elderly groups should be significantly higher than that in young population. The DM prevalence of each group in big cities is higher than that in medium and small cities.

Association of angiotensin converting enzyme gene I/D polymorphism with type 2 diabetes mellitus.

OBJECTIVE: To investigate the association of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism with type 2 diabetes mellitus (T2DM). METHODS: Two hundred and nine patients with T2DM diagnosed based on the criteria for diabetes mellitus in 1999 by WHO and 221 controls were recruited from general population of Dongcheng District in Beijing. All subjects were genotyped for the I/D polymorphism of ACE gene by PCR-fragment length polymorphism (FLP) assay. Blood pressure, levels of plasma glucose, lipids and serum insulin were determined. Body mass index (BMI), waist-hip ratio (WHR) and homeostasis model assessment-insulin resistance index (HOMA-IR) were calculated. RESULTS: The genotype frequencies for ACE genes DD, ID, and II were 19.1%, 42.1%, and 38.8% in patients, respectively, and 9.6%, 49.4%, and 41.0% in controls, respectively. The ACE DD genotype frequency was significantly higher in patients than in controls (chi2 = 7.61, P = 0.022). Multivariate logistic regression analysis showed that the ACE DD genotype was a risk factor for T2DM, with the OR of 2.35 (95% CI 1.17-4.71) adjusted for age, sex, BMI, WHR, blood pressure, and serum cholesterol levels. CONCLUSION: The ACE DD genotype is associated with the increased susceptibility to type 2 diabetes mellitus.

[A description on the Chinese national nutrition and health survey in 2002].

OBJECTIVE: To describe the status of nutrition and health related indices in the Chinese population. METHODS: A stratified multi-stage cluster sampling was used from 31 provinces, autonomous regions, and municipalities. The survey was done in 2002, including data gathered from questionnaires, interviews, physical examinations, measurement of biochemical indices, and dietary investigation. RESULTS: Cereals accounted for 48.5% of all the sources of energy in urban and 61.4% in rural populations. Daily mean percentages of calories for total fat were 35.0% in urban and 27.5% in rural areas. The prevalence rates of stunting and underweight were 14.3% and 7.8% respectively in young children under 5-year-old. The prevalence of vitamin A deficiency was 9.3% in Chinese children aged 3-12 years old. The total prevalence of anemia was 15.2% in general population of all ages. The prevalence of anemia in young adults was significantly higher in women than in men. The total prevalence rates of overweight and obesity were 17.6% and 5.6%, respectively. The prevalence rates of hypertension, diabetes, hypercholesteremia, hypertriglyceridemia, or low serum high density lipoprotein cholesterol were 18.8%, 2.6%, 2.9%, 11.9%, 7.4% respectively in Chinese adults aged 18 and over. The rates of awareness, treatment, and under control among hypertensives were 30.2%, 24.7%, and 25.0%, respectively. Significant regional and age differences were revealed in the dietary habit and the prevalence of various diseases. The prevalence of diseases associated with malnutrition were higher in rural than in urban areas. In contrast, the prevalence of conditions associated with overconsumption and inappropriate dietary patterns were higher in urban than in rural populations. CONCLUSION: Chinese people were currently suffering from both problems on nutrition related issues and burdens of diseases which were characterized in nutrient deficiencies and overconsumption, malnutrition and noncommunicable conditions associated with overconsumption and inappropriate diet. The difference of nutrition and health status between rural and urban people was also seen.

[Leptin and clustering of the components of risk factors for metabolic syndrome].

OBJECTIVES: To evaluate relationship between serum level of leptin and the components of risk factors for metabolic syndrome and to analyze the characteristics and laws of clustering of the risk factors. METHODS: Totally, 795 non-diabetic adult Chinese subjects (691 men and 104 women, aged 40 - 75 years) from a diabetes prevalence survey in 2000 were involved in this study. Measurements included serum levels of true insulin (TI), leptin, fasting lipids, fasting glucose (FBG) and 2 h postchallenge glucose, as well as seated blood pressure (BP), body mass index (BMI), ratio of waist circumference to hip circumference (WHR), calculated quantitative insulin sensitivity check index (QUICKI), etc. Relationship between serum level of leptin and all the variables mentioned above was studied by statistical methods such as factor analysis, etc. RESULTS: Serum level of leptin in the study subjects increased with the number of components of abnormal metabolism they had. Detection rates of obesity, hypertension, dyslipidemia and metabolic syndrome were significantly higher in those with the upper tertile of serum leptin level than in those with the lower tertile. Factor analysis revealed that variation of the 11 variables including serum level of leptin was affected by the three factors, i.e., the central factor associated with BMI, WHR, FTI, QUICKI and higher serum level of triglyceride (TG) and lower serum level of high-density lipoprotein-cholesterol (HDL-C), the glucose intolerance factor loaded with blood glucose level, FTI, QUICKI and higher serum level of TG (in women only) and the hypertension factor loaded with blood pressure and BMI (in men only), which could explain 62.0% and 66.7% of total variance in men and women, respectively, and higher serum level of TI and insulin resistance also loaded with both the central factor and glucose tolerance factor. CONCLUSIONS: Serum level of leptin was significantly associated with the key markers of metabolic syndrome. Hyperleptinaemia could be a new component of metabolic syndrome. Clustering of the risk factors for metabolic syndrome could be affected by many factors, and although insulin resistance played an important role in it, insulin resistance alone could not explain its etiology.

[Study on prevalence rates of hypertension and chronic diabetic complications of in-patients with diabetes].

OBJECTIVE: To understand the relationship between prevalence rates of chronic diabetic complications and related macro-vascular diseases and hypertension, to provide evidence for diabetes prevention and control. METHODS: To retrospectively analyze the clinical and laboratory data on 24 496 in-patients with diabetes during Jan. 1, 1991 to Dec. 31, 2000 from 30 provinces, municipalities and autonomous regions. RESULTS: The prevalence rate of hypertension was 31.95%. The prevalence rates of other chronic diabetic complications and related macro-vascular diseases were 12.2% for cerebrovascular diseases, 15.9% for cardiovascular diseases, 5.0% for lower extremity vascular diseases, 34.3% for eye diseases, 33.6% for nephropathy and 60.3% for neuropathy, with a total rate of chronic diabetic complications and macro-vascular diseases of 73.2%. Hypertension was related with all kinds of chronic diabetic complications and macro-vascular diseases odds ratio (OR) of related systolic blood pressure was 1.148 - 1.866, and OR related diastolic was 1.141 - 1.242. CONCLUSIONS: The prevalence rates of chronic diabetic complications and related macro-vascular diseases of in-patients with diabetes mellitus were much higher than those of non-diabetics, and was close to the levels seen in the western countries. Hypertension, especially high systolic blood pressure was the most important risk factor of chronic diabetic complications and the related macro-vascular diseases.

[Epidemiological survey of chronic vascular complications of type 2 diabetic in-patients in four municipalities].

OBJECTIVE: To provide an epidemiological description and risk factors of chronic vascular complications of type 2 diabetic in-patients in four municipalities including Beijing, Shanghai, Tianjin, and Chongqing. METHODS: Data of the study came from 3,469 Type 2 diabetic in-patients from 1991 to 2000 in 10 medical centers of Beijing, Shanghai, Tianjin, and Chongqing. A variety of parameters of in-patients were evaluated retrospectively to know the prevalence and risk factors of chronic vascular complications in the study patients. RESULTS: Overall, the detailed prevalence of chronic vascular complications is listed as follows: diabetic retinopathy 31.5%, diabetic nephropathy 39.7%, diabetic neuropathy 51.1%, hypertension 41.8%, coronary heart disease (CHD) 25.1%, cerebral vascular disease (CVD) 17.3%, vessel complication of lower limbs 9.3%. Multivariate logistic regression analysis shows that diabetes family history, duration of diabetes (> 5 years), and systolic blood pressure (> 125 mmHg) are the risk factors for diabetic retinopathy; duration of diabetes (> 5 years), systolic blood pressure (> 125 mmHg), LDL-C (> 3.12 mmol/L), and triglyceride (> 1.70 mmol/L) are the risk factors for diabetic nephropathy; age (> 45 years), duration of diabetes (> 5 years), HbA1C (> 7.0%), systolic blood pressure (> 125 mmHg), and LDL-C (> 3.12 mmol/L), are the risk factors for CHD; age (> 45 years), duration of diabetes (> 5 years), systolic blood pressure (> 125 mmHg), and triglyceride (> 1.70 mmol/L) are the risk factors for CVD. CONCLUSION: In order to improve patients' outcome, multiple metabolic controls in type 2 diabetic patients are urgently needed, which include decreasing glycemia, reducing hypertension and improving lipid levels.