Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice.

INTRODUCTION: Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. METHODS: Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate were then measured using ultra-performance liquid chromatography with mass spectrometry. RESULTS: CA1 neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third, and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. CONCLUSION: Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.

Calcifediol (25-hydroxyvitamin D) improvement and calcium-phosphate metabolism of alendronate sodium/vitamin D3 combination in Chinese women with postmenopausal osteoporosis: a post hoc efficacy analysis and safety reappraisal.

BACKGROUND: Vitamin D (VD) insufficiency or deficiency is a frequent comorbidity in Chinese women with postmenopausal osteoporosis (PMO). The present study aimed to investigate 25-hydroxyvitamin D [25(OH) D] improvement and calcium-phosphate metabolism in Chinese PMO patients treated with 70 mg of alendronate sodium and 5600 IU of vitamin D3 (ALN/D5600). METHODS: Chinese PMO women (n = 219) were treated with 12-month ALN/D5600 (n = 111) or calcitriol (n = 108). Changes in 25(OH) D at month 12 were post hoc analyzed by the baseline 25 (OH) D status using the longitudinal analysis. The main safety outcome measures included serum calcium and phosphate and 24-h urine calcium, and the repeated measures mixed model was used to assess the frequencies of the calcium-phosphate metabolic disorders. RESULTS: Absolute change in mean serum 25(OH) D level was the greatest in VD-deficient patients and least in VD-sufficient patients at months six and 12 (both, P < 0.01). Serum calcium level remained significantly lower in the ALN/D5600 treatment group than in the calcitriol treatment group throughout the 12 months. Mean 24-h urine calcium slightly increased in the ALN/D5600 treatment group and significantly increased in the calcitriol treatment group (+ 1.1 and + 0.9 mmol/L at months six and 12; both, P < 0.05). Calcitriol treatment was associated with more frequent hypercalciuria at month six (9.4% vs. 18.5%, P = 0.05), but not at month 12 (12.3% vs. 13.0%). CONCLUSION: Baseline VD status predicted 25(OH) D improvement in PMO patients on 12-month ALN/D5600 treatment. The daily use of 0.25 µg of calcitriol was associated with more frequent hypercalciuria at month six, compared to ALN/5600 treatment, necessitating the safety re-evaluation of calcitriol at a higher dosage.

Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Association Between Nickel Exposure and Metabolic Syndrome: Data from NHANES 2017-2018.

Previous studies have found a possible association between nickel and metabolic syndrome (MetS), but with conflicting results. No studies have determined whether nickel exposure increases the prevalence of MetS in the general U.S. population. Therefore, we used data from the National Health and Nutrition Examination Survey (NHANES) to assess the association between urinary nickel and MetS. Since urinary nickel levels were presented as a skewed distribution, they were normalized using a logarithmic transformation. Weighted multivariate logistic models, restricted cubic spline, threshold effect analysis, and subgroup analyses were used to examine the association between urinary nickel concentration and the risk of MetS and its components. Based on data from 1577 participants, individuals in the second, third, and fourth quartiles of urinary nickel had an adjusted OR for MetS of 1.42 (95% CI: 0.88, 2.28), 2.00 (95% CI: 1.22, 3.28), and 1.68 (95% CI: 1.05, 2.70), respectively, representing an inverted "L"-shaped nonlinear dose-response relationship with an inflection point at 0.2141 ng/L. Patients over the age of 40, males, less educated, and smokers are more susceptible to nickel exposure. In addition, there were significant associations between nickel and most components of the MetS, with the strongest to weakest correlations being high fasting glucose, reduced high-density lipoprotein, abdominal obesity, and elevated blood pressure; however, there was no significant correlation between nickel and hyperlipidemia. In conclusion, environmental nickel exposure increases the prevalence of MetS in U.S. adults, particularly in males over 40 years of age, those with less education, and smokers.

Efficacy and safety of combination therapy with vildagliptin and metformin versus metformin up-titration in Chinese patients with type 2 diabetes mellitus: study design and rationale of the vision study.

BACKGROUND AND AIM: Limitations of the currently recommended stepwise treatment pathway for type 2 diabetes mellitus (T2DM), especially the failure of monotherapies to maintain good glycemic control, have prompted use of early, more aggressive combination therapies.The VISION study is designed to explore the efficacy and safety of vildagliptin as an add-on to metformin therapy compared with up-titration of metformin monotherapy in Chinese patients with T2DM. METHODS: VISION, a 24-week, phase 4, prospective, randomized, multicenter, open-label, parallel-group study, will include 3312 Chinese T2DM patients aged ≥18 years who are inadequately controlled (6.5% >HbA1c ≤9%) by metformin (750-1000 mg/day). Eligible patients will be randomized to receive either vildagliptin plus metformin or up-titration of metformin monotherapy (5:1). Patients will also be subgrouped (1:1:1:1) based on their age and body mass index (BMI): <60 years and <24 kg/m²; <60 years and ≥24 kg/m²; ≥60 years and <24 kg/m²; and ≥60 years and ≥24 kg/m². CONCLUSION: The VISION study will test the hypothesis that early use of combination therapy with vildagliptin and metformin will provide good glycemic control and will be better tolerated than up-titration of metformin monotherapy. The study will also correlate these benefits with age and BMI.

[The design and baseline characteristics of a phase III study to evaluate the efficacy and safety of alogliptin versus placebo in type 2 diabetes mellitus in Mainland China].

OBJECTIVE: To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events. RESULTS: A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced. CONCLUSION: The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.

Association between Chinese visceral adiposity index and metabolic-associated fatty liver disease in Chinese adults with type 2 diabetes mellitus.

Objective: The purpose of the study was to determine the correlation of the Chinese visceral adiposity index (CVAI) with metabolic-associated fatty liver disease (MAFLD) in Chinese adults with type 2 diabetes mellitus (T2DM). Materials/methods: In this cross-sectional study, data on sociodemographic characteristics, laboratory test results, coexisting diseases, and medical therapy were collected and analyzed. Multivariate logistic regression analyses were used to examine the correlation between CVAI and MAFLD. In order to investigate the correlation between CVAI on a continuous scale and MAFLD, a restricted cubic spline (RCS) was used. Results: A total of 679 participants were included in this study. There were 251 female participants and 428 male participants, with a median age of 55 years. In the multivariate logistic regression model, diastolic blood pressure, duration of diabetes, glycated hemoglobin, hemoglobin, alanine transaminase, aspartate aminotransferase, gamma -glutamyl transferase, albumin, blood urea nitrogen, total cholesterol, low-density lipoprotein cholesterol, statin use and metformin use were adjusted, and an evident increase in the odds ratios of MAFLD from the lowest to the highest CVAI quartile was found (P value for trend < 0.001). Moreover, the RCS curves revealed a positive correlation between CVAI and MAFLD. Conclusions: The CVAI is positively correlated with MAFLD and may be an indicator with diagnostic value for MAFLD in clinical practice in type 2 diabetic patients.

Association Between High-Sensitivity C-Reactive Protein and Diabetic Kidney Disease in Patients With Type 2 Diabetes Mellitus.

Objective: High-sensitivity C-reactive protein (hs-CRP) is an inflammatory marker. This study aimed to identify the correlation between hs-CRP levels and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Materials/Methods: This cross-sectional and observational study included 927 patients with T2DM. We collected the data of patients based on their medical data, including sociodemographic characteristics, concomitant diseases, laboratory results, and medical therapy. Multivariate logistic regression analysis was conducted to assess the relationship between hs-CRP levels and DKD. A restricted cubic spline (RCS) was used to assess the correlation of hs-CRP levels on a continuous scale with the DKD. Results: In total, 927 patients were recruited in our study. The median age of the recruited patients was 55 years, and there were 346 female patients and 581 male patients. The hs-CRP levels were evidently higher in patients with DKD than those without DKD. After adjusting for age, sex, diastolic blood pressure, systolic blood pressure, body mass index, neck circumference, waist circumference, hypertension, duration of diabetes, common carotid artery plaque, fasting plasma glucose, glycated hemoglobin, hemoglobin, erythrocyte, leukocyte, γ-glutamyl transferase, albumin, urea nitrogen, uric acid and triglyceride, a significant increase in the odds ratios (ORs) for DKD in the fourth hs-CRP quartile compared with the first quartile was observed (P value for trend= 0.003), and the ORs (95% confidence intervals) in the fourth quartile of hs-CRP were 1.968 (1.244-3.114) for DKD compared to the first quartile.. Moreover, the RCS curves presented a positive association between hs-CRP and DKD in total subjects, male subjects and female subjects, respectively. Conclusions: The results of our study indicated that hs-CRP levels were significantly and positively correlated with the presence of DKD, which may provide predictive and diagnostic values in clinical practice.

Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease.

Graves' disease (GD) is one of the most common human autoimmune diseases, and recent data estimated a prevalence of clinical hyperthyroidism of 0.25-1.09% in the population. Several reports have linked GD to the region 5q12-q33; and a locus between markers D5s436 and D5s434 was specifically linked to GD susceptibility in the Chinese population. In the present study, association analysis was performed using a large number of single-nucleotide polymorphisms (SNPs) at this locus in 2811 patients with GD recruited from different geographic regions of China. The strongest associations with GD in the combined Chinese Han cohorts were mapped to two SNPs in the promoter (pSNP) of SCGB3A2 [SNP76, rs1368408, P = 1.43 x 10(-6), odds ratio (OR) = 1.28 and SNP75, -623 - -622, P = 7.62 x 10(-5), OR = 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)+SNP74 (rs6882292) or SNP76+SNP75 (-623 approximately -622, AG/T) variants are correlated with high disease susceptibility (P = 0.0007, and P = 0.0192, respectively) in this combined Chinese Han cohort. Furthermore, these haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.

Decreased Microstructural Integrity of the Central Somatosensory Tracts in Diabetic Peripheral Neuropathy.

CONTEXT: Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown. OBJECTIVE: This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN. METHODS: A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients. RESULTS: The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders. CONCLUSION: Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN.

[3T3L1 adipocytes induce rat beta-cell dysfunction].

OBJECTIVE: To investigate the integrated effects of adipocytes on rat beta-cells, differentiated 3T3L1 adipocytes and rat islet cells co-culture system was established. METHODS: There were two groups: control group (SD rat islet cells) and co-culture group (islet cells and 3T3L1 adipocytes coculture system). Islet cells were obtained for determination of (1) insulin secretion and insulin content; (2) mRNA expressions of GLUT2, GCK and Kir6.2; (3) protein expressions of IR-beta, IRS-1 and their tyrosine phosphorylation level. RESULTS: (1) At low glucose, insulin secretion of co-culture group increased compared with that of control group (0.79 +/- 0.35) ng x h(-1) x ml(-1) islet vs. (0.38 +/- 0.09) ng x h(-1) x ml(-1) x islet, P = 0.028. At high glucose, insulin secretion of those two groups was almost at the same level (P = 0.760). Compared with control group (2.84 +/- 0.92), stimulation index (SI, insulin release at high glucose/ low glucose) of co-culture system decreased to (1.57 +/- 0.61, P = 0.04). And the insulin content of the both groups was almost at the same level (P = 0.102). (2) The mRNA of GCK, GLUT2 and Kir6.2 in co-culture group downregulated to (0.27 +/- 0.11, P = 0.01), (0.34 +/- 0.24, P = 0.009) and (0.41 +/- 0.09, P = 0.003) compared with control group (mRNA = 1). (3) The protein levels of IR-beta, IRS-1 and their tyrosine phosphorylation decreased in co-culture system. CONCLUSIONS: 3T3L1 adipocytes are involved in beta-cell dysfunction, which may facilitate the development of type 2 diabetes. The effects may be mediated by multiple pathways, which include downregulation of GSIS related gene expressions and suppression of islet cell insulin signaling.

Postpartum Follow-Up of Patients with Subclinical Hypothyroidism During Pregnancy.

Background: Subclinical hypothyroidism (SCH) in pregnancy is associated with adverse pregnancy and perinatal outcomes. However, few studies have investigated the evolution of postpartum thyroid function in these women. This study aimed to determine the postpartum outcomes of SCH during pregnancy and the clinical and biochemical factors related to the evolution of long-term hypothyroidism. Methods: A total of 393 women diagnosed with SCH during pregnancy (defined as thyrotropin [TSH] >4.0 µIU/mL with normal free thyroxine levels according to the 2017 American Thyroid Association guidelines) were prospectively followed up after delivery. Among them, 216 underwent long-term follow-up [median (interquartile range) follow-up time: 11 (7-19) months] postpartum. The clinical and biochemical characteristics of the women with long-term postpartum hypothyroidism and euthyroidism were compared. Linear mixed model (LMM) was used to explore the risk factors for longitudinal changes of TSH, and logistic regression analysis was employed to identify the independent predictors of long-term postpartum hypothyroidism. Results: The probability of long-term hypothyroidism after delivery in SCH during pregnancy was 38.9%. Among the subjects with normal thyroid function 6-week postpartum, 28.2% developed hypothyroidism during long-term follow-up. The LMM showed that gestational age at the time of SCH diagnosis (estimate: -0.018, p = 0.004) and thyroid peroxidase antibodies (TPOAb) (estimate: 0.001, p = 0.020) were significantly associated with longitudinal changes of TSH. The logistic regression model showed that TPOAb positive both during pregnancy and six-week postpartum was a risk factor for long-term hypothyroidism after delivery (odds ratio = 4.686 [95% confidence interval 1.242 to 17.680], p = 0.023). Conclusions: More than one-third of patients with SCH during pregnancy had persistent hypothyroidism after delivery. We recommend that patients with TPOAb positive both during pregnancy and six-week postpartum undergo close follow-up to detect persistent hypothyroidism, especially before the next pregnancy.

[A comparison of the efficacy and safety of domestic orlistat and imported orlistat in Chinese overweight and obese patients].

OBJECTIVE: To compare the clinical efficacy and safety of domestic orlistat and imported orlistat in Chinese overweight and obese patients. METHODS: In a randomized, double-blinded and positive-controlled study, 228 adults (BMI 24- < 40 kg/m(2)) evaluated at seven research centers were randomized to receive domestic orlistat or imported orlistat 120 mg 3 times a day with an energy-controlled diet for 24 weeks. RESULTS: After 24 weeks, domestic orlistat treated patients got significant weight-loss (5.0 +/- 3.7) kg, which was comparable with that of imported orlistat treated patients (4.5 +/- 3.5) kg (P = 0.3922). Compared with the findings before treatment, there was significant decrease of systolic blood pressure (4.4 +/- 11.5) mm Hg (1 mm Hg = 0.133 kPa) and serum levels of TC (0.54 +/- 0.79) mmol/L and LDL-C (0.32 +/- 0.64) mmol/L in the domestic orlistat treated group (compared with levels of baseline, P < 0.0001). There was no significant difference between the two groups in the changes of blood pressure and lipid levels. Both groups had similar adverse event profiles, most of which were mild and transient gastrointestinal events. There were no serious adverse events in both groups. CONCLUSIONS: Domestic orlistat combined with a light low-energy diet promoted significant weight loss, which was comparable with that of imported orlistat after 24 weeks of treatment. There was also improvement in blood pressure and serum levels of TC and LDL-C. Domestic orlistat was as effective and safe as imported orlistat in the treatment of obesity.

[A multi-center clinical study of the reference value of serum glycated albumin].

OBJECTIVE: To set up the reference value of serum glycated albumin (GA) in Chinese for using in clinical practice through a multi-center clinical trial. METHODS: Three hundred and eighty individuals with normal weight and normal glucose regulation, including 183 males and 197 females ranging from 20 to 69 years, were recruited from 10 hospitals in China Serum GA levels were measured with liquid enzymatic method. RESULTS: (1) The GA level of the 380 subjects was (14.5 +/- 1.9)%. When dividing these subjects by age into 3 subgroups, there was no difference in the GA levels among the 3 subgroups (P > 0.05). Compared with the women, the men had higher GA level in the first subgroup aging from 20 to 39 (P = 0.028). However, no significant difference was detected after adjusting with BMI as confounder. (2) When dividing those subjects by BMI into 3 subgroups, with BMI ranging from 18.5-20.9 kg/m2 21.0-22.9 kg/m2 and 23.0-24.9 kg/m2 respectively, we came to the following results: for men, there was no difference in the GA levels among the 3 subgroups (P > 0.05), but for women, the GA level of the first subgroup was higher than that of the second subgroup (P = 0.024). (3) The level of GA in the 2.5th to 97.5th percentile was 10.8%-17.1%. (4) Sixty normal subjects were chosen to repeat evaluation of GA levels after 2-3 weeks and the GA levels were of no difference (P > 0.05). CONCLUSION: The normal range of serum GA for the Chinese population could be suggested at 11%-17%.

Clinical characteristics associated with bone mineral density improvement after 1-year alendronate/vitamin d3 or calcitriol treatment: Exploratory results from a phase 3, randomized, controlled trial on postmenopausal osteoporotic women in China.

Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO).In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis.In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (ß = -0.00084, P < .01), dietary calcium (ß = -0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (ß = -0.000469, P = .0016), but positively with body mass index (BMI) (ß = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (ß = 0.0023, P = .02), baseline P1NP (ß = 0.00035, P = .0067), history of prior vertebral fracture(s) (ß = 0.034, P < .0001) and baseline serum 25(OH)D level (ß = -0.00083, P = .02).The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.

Metabolic syndrome and non-alcoholic fatty liver disease: Asian definitions and Asian studies.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), as conventionally recognized, is a metabolic disorder largely confined to residents of affluent industrialized Western countries. However, obesity and insulin resistance are not restricted to the West, as witnessed by their increasingly universal distribution. In particular, there has been an upsurge in metabolic syndrome in the Asia-Pacific region, although there are critical differences in the extent of adiposity between Eastern and Western populations. DATA SOURCES: An English-language literature search using PubMed (1999-2007) on obesity, metabolic syndrome and NAFLD, focusing on Asian definitions and Asian studies. RESULTS: NAFLD appears to be of long-standing insulin resistance and likely represents the hepatic manifestation of the metabolic syndrome. With insulin resistance as a common factor, the disease is associated with atherosclerosis and cardiovascular risk. All features of the metabolic syndrome and related events are assessed for practical management of NAFLD, although the criteria for the diagnosis of obesity and central obesity differ across racial groups. CONCLUSIONS: The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension and ultimately metabolic syndrome, puts a very large population at risk of developing NAFLD in the coming decades. The simultaneous identification and appropriate treatment of the components of metabolic syndrome are crucial to reduce hepatic as well as cardiovascular morbidity and mortality.

A complex heterozygous mutation of His373Leu and Asp487-Ser488-Phe489 deletion in human cytochrome P450c17 causes 17alpha-hydroxylase/17,20-lyase deficiency in three Chinese sisters.

Cytochrome P450c17 deficiency is one of the rare forms of enzyme disorders in steroid biosynthesis, resulting from defects in 17alpha-hydroxylase and 17,20-lyase activities. The disease is caused by the mutations in CYP17 gene, inherited in an autosomal recessive pattern. We reported a Chinese family with three sisters suffering from P450c17 deficiency based on their clinical features and molecular genetics. The patients were found to be compound heterozygotes with two different mutations. Screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), a heterozygous point mutation His373Leu was detected in the exon 6 of CYP17 gene which was proved to be derived from paternal allele. The other allele contained nine-base pair deletion, located in exon 8, eliminating codons 487-489 (Asp-Ser-Phe) near the carboxy-terminus of P450c17. The mother and the brother have been demonstrated to be carriers of deletion mutation through restriction enzyme analysis. Both mutations have been reported previously in Asia. This is the first report of the molecular genetic study of 17alpha-hydroxylase/17,20-lyase deficiency in mainland China with a novel compound heterozygous mutation.

Unilateral gynecomastia and hypokalemic periodic paralysis as first manifestations of Graves' disease.

A 39-year-old Chinese man presented to the study hospital with right-sided gynecomastia. Underlying Graves' disease was not diagnosed until recurrent episodes of hypokalemic periodic paralysis were observed. The estradiol (E2) and progesterone levels and the E2-to-testosterone (T) (E2/T) ratio of the patient were elevated before treatment. Immediate intravenous potassium supplementation was started to reverse the paralysis. Additionally, antithyroid drugs were administered to restore a euthyroid state. After treatment, the patient gained strength. Gynecomastia regressed with a return to the euthyroid state; the E2 and progesterone levels normalized and the plasma E2/T ratio declined. In addition to the classic symptoms, some atypical symptoms of Graves' disease may also occur. One of the challenges lies in recognizing the underlying etiology. Early diagnosis and appropriate treatment can avoid unnecessary investigations and serious cardiopulmonary complications.

Glyoxalase I and aldose reductase gene polymorphisms and susceptibility to carotid atherosclerosis in type 2 diabetes.

AIMS: To investigate the association of polymorphisms of glyoxalase I (GLO1) A419C, GLO1 C-7T, and aldose reductase C-106T with type 2 diabetes and diabetic carotid atherosclerosis in a Chinese Han population. METHODS: The study population included 362 patients with type 2 diabetes and 301 nondiabetic control subjects. Genetic analyses were performed using either the Taqman polymerase chain reaction or direct sequencing. All patients with diabetes underwent carotid ultrasonography to assess the intima-media thickness and the presence of atherosclerotic plaques. RESULTS: There were no differences between the genotype frequencies of GLO1 A419C, GLO1 C-7T, and aldose reductase C-106T polymorphisms, in the control and diabetic groups. The value of mean carotid intima-media thickness and the prevalence of carotid atherosclerotic plaques were significantly increased in patients with type 2 diabetes with the GLO1-7CC genotype compared with those with the -7CT and TT genotypes (permutation p=0.003 and 0.031, respectively). Multiple regression analysis showed that the GLO1-7CC genotype was an independent determinant of carotid intima-media thickness (ß=0.12, p=0.014), but not an independent risk factor for carotid atherosclerotic plaques (odds ratio [OR]=1.74, 95% CI 0.89-3.42, p=0.10) in patients with type 2 diabetes. CONCLUSIONS: The GLO1 C-7T polymorphism is associated with carotid atherosclerosis in Chinese patients with type 2 diabetes.

A genome-wide association study identifies two new risk loci for Graves' disease.

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.