Prevalence of thyroid dysfunction in older Chinese patients with type 2 diabetes-A multicenter cross-sectional observational study across China.

Type 2 diabetes [T2D] and thyroid dysfunction [TD] often co-occur, have overlapping pathologies, and their risk increases with age. Since 1995, universal salt iodization has been implemented in China to prevent disorders caused by iodine deficiency. However, after two decades of implementation of universal salt iodization, the prevalence of TD in elderly Chinese patients with T2D is not well described and may have been underestimated. We conducted a questionnaire-based survey across 24 endocrinology centers in China between December 2015 and July 2016. Demographic and clinical data from 1677 patients with T2D were obtained and analyzed to examine the prevalence of TD along with T2D in these patients. We assessed TD prevalence according to the four TD subtypes [subclinical hypothyroidism, clinical hypothyroidism, subclinical hyperthyroidism, and clinical hyperthyroidism], TD history, gender, and age. The diagnosis rates were calculated for TD and also for the TD subtype. The number of patients reaching treatment goals for T2D [hemoglobin A1c <7%] and TD [normal free thyroxine and thyroid-stimulating hormone [TSH]] and the incidences of complications and comorbidities were recorded. Among the enrolled patients with T2D [N = 1677], TD was diagnosed in 23.79% [399/1677] out of which 61% (245/399) were previously diagnosed and 38.59% (154/399) were newly diagnosed cases. Subclinical hypothyroidism, clinical hypothyroidism, subclinical hyperthyroidism, and clinical hyperthyroidism were reported in 4.89%, 9.3%, 1.13%, and 3.16% of the total population, respectively. Among patients previously diagnosed with TD, the incidence in women [166/795; 20.88%] was higher than in men [79/882; 8.96%]. The treatment goals for TD and T2D were attained in 39.6% [97/245] and 34.41% [577/1677] of the cases, respectively. Diabetic complications and comorbidities were reported in 99.7% of patients, with peripheral neuropathy being the most common [43.46%] followed by cataract [24.73%]. We had found that the incidences of dyslipidemia, elevated LDL levels, and osteoporosis were significantly higher in patients with TD than those without TD. TD is underdiagnosed in elderly Chinese patients with T2D.

A systematic review and meta-analysis of the risk of diarrhea associated with vandetanib treatment in carcinoma patients.

BACKGROUND AND PURPOSE: Vandetanib is a promising anticancer targeted agent for treating advanced carcinomas, such as non-small-cell lung cancer, small-cell lung cancer, breast cancer, malignant glioma, hepatocellular cancer, and unresectable, locally advanced, or metastatic medullary thyroid cancer. However, diarrhea is a frequently reported adverse event. The incidence of vandetanib-associated diarrhea varies extensively in different study populations and has not been carefully estimated. This systematic review and meta-analysis of clinical trials aims to figure out the overall risks of all-grade and high-grade diarrhea during vandetanib treatment and get a better understanding of its prediction and management. MATERIALS AND METHODS: A comprehensive search was performed in EMBASE, PubMed, and Cochrane Library for clinical trials studying vandetanib and diarrhea prior to April 2015. Eligible articles were selected according to the inclusion criteria. Data were extracted to calculate the summary incidence of all-grade and high-grade diarrhea caused by vandetanib treatment. RESULTS: Thirteen clinical trials that involved 3,264 patients were included in this meta-analysis. The overall incidences of all-grade and high-grade diarrhea caused by vandetanib treatment were 52.1% (95% confidence interval [CI], 48.3%-55.8%) and 5.6% (95% CI, 4.4%-76.7%), respectively. The risk ratios of the all-grade and high-grade diarrhea for vandetanib arm versus control arm were 1.932 (95% CI, 1.746-2.138; P<0.001) and 3.190 (95% CI, 2.061-4.938; P<0.001), respectively. Studies with small-cell lung cancer demonstrated the highest incidence of all-grade diarrhea (78.85%) and high-grade diarrhea (17.31%), whereas the lowest incidences of all-grade (42.11%) and high-grade (2.67%) diarrhea are seen in patients with hepatocellular carcinoma and non-small-cell lung cancer, respectively. CONCLUSION: Our findings demonstrate that the administration of vandetanib leads to a significantly increased risk of diarrhea, which varies in different carcinoma patients. Early recognition and timely management may be key factors to avoid dose reduction, drug interruption, and drug discontinuation, which is significant to maximize the treatment benefits.

Exendin-4 promotes proliferation and differentiation of MC3T3-E1 osteoblasts by MAPKs activation.

Glucagon-like peptide-1 (GLP1) and its receptor agonist have been previously reported to play a positive role in bone metabolism in aged ovariectomized rats and insulin-resistant models. However, whether GLP1 has a direct effect on the proliferation and differentiation of osteoblasts or any cellular mechanism for this potential role is unknown. We examined the effects of the GLP1 receptor agonist exendin-4 on the proliferation, differentiation, and mineralization of mouse osteoblastic MC3T3-E1 cells. GLP1 receptor was detected in MC3T3-E1 cells by polymerase chain reaction (PCR) and Western blot assay. Cell proliferation was assessed using MTT assay, revealing that exendin-4 increased cell proliferation at effective concentrations between 10(-10) and 10(-5) M. Quantitative PCR analysis showed that exendin-4 increased the mRNA expression of the differentiation markers alkaline phosphatase (ALP), collagen-1 (COL1), osteocalcin (OC), and runt-related transcription factor 2 (RUNX2) under osteogenic conditions. Alizarin red staining confirmed that 10(-7) M exendin-4 increased osteoblast mineralization by 18.7%. Exendin-4 upregulated the phosphorylation of ERK1/2, p38, and JNK, with the peak effect at 1.5 h in the Western blot analysis. The use of selective MAPK inhibitors, namely PD98059, SB203580, and SP600125, blocked the effects of exendin-4 on kinase activation (ERK1/2, p38, and JNK), as well as cell proliferation and differentiation in MC3T3-E1 cells. These findings demonstrate that exendin-4 promotes both the proliferation and differentiation of preosteoblasts MC3T3-E1 via activation of the MAPK pathway.

Transmembrane protease serine 4 promotes thyroid cancer proliferation via CREB phosphorylation.

BACKGROUND: Transmembrane protease serine 4 (TMPRSS4), one of the type II transmembrane serine proteases (TTSPs), is elevated in various cancers and is associated with multiple malignant phenotypes. However, the expression pattern and biologic significance of TMPRSS4 in thyroid cancer are largely unknown. In this study, we investigated the expression of TMPRSS4 in thyroid cancer and assessed the pro-proliferative role of TMPRSS4 in thyroid cancer. METHODS: Immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of TMPRSS4 in thyroid cancer. We evaluated in vitro cell proliferation using MTT, colony formation, anchorage-independent growth, flow cytometry analysis, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays. Western blot, real-time RT-PCR, and luciferase assays were conducted to reveal the underlying mechanisms. RESULTS: TMPRSS4 is overexpressed in thyroid cancer and is associated with the grade of malignancy. Depletion of TMPRSS4 in thyroid cancer cells significantly suppressed proliferation. Moreover, the proliferation of thyroid cancer cells with TMPRSS4 overexpression was significantly enhanced. We also show that cyclic adenosine monophosphate response element-binding protein (CREB)-cyclin D1 signaling mediates, at least partially, the role of TMPRSS4 in thyroid cancer cell proliferation. CONCLUSIONS: TMPRSS4 is overexpressed in thyroid cancer and TMPRSS4-CREB signaling is needed to sustain thyroid cancer cell proliferation.

Down-regulation of miR-144 promotes thyroid cancer cell invasion by targeting ZEB1 and ZEB2.

Thyroid cancer is the most common endocrine malignancy, and its incidence has increased rapidly worldwide. The molecular mechanisms underlying thyroid cancer tumorigenesis still need to be further investigated. MicroRNAs (miRNAs), short RNA molecules of approximately 22 nucleotides in length, play crucial roles in tumorigenesis. In the present study, we found that the expression of miR-144 was significantly down-regulated in thyroid cancer as compared with that in normal thyroid tissues, suggesting that miR-144 may be involved in thyroid cancer tumorigenesis. Moreover, our results showed that restoration of miR-144 in K1 and WRO thyroid cancer cells could suppress the invasion and migration capability of these cells. We also demonstrated that miR-144 suppressed the expression of ZEB1 and ZEB2, two E-cadherin suppressors, by directly binding to their 3'-untranslated regions. Furthermore, restoration of ZEB1 or ZEB2 partially rescued the miR-144-induced inhibition of cell invasion. These data suggest miR-144 function as a tumor suppressor in thyroid cancer.

[Palmitate induced apoptosis in MC3T3-E1 cell by activation of nuclear factor-kappa B].

OBJECTIVE: To explore whether palmitate-induced apoptosis of osteoblastic MC3T3-E1 cell is mediated by an activation of nuclear factor-kappa B (NF-κB). METHODS: Cell viability was assessed with methyl thiazolyl tetrazolium (MTT) assay and cell apoptosis by Hochest 33258 staining. Palmitate was added at different timepoints and dosages.Western blot was used to evaluate the expression levels of IκBα, p-NF-κB p65 and NF-κB p65 protein. RESULTS: Palmitate led to a dose- and time-dependent decreases in cell viability and increase in cell apoptosis. Cell viability dropped to 54% and cleaved caspase-3 increased 3.1-fold in cells treated with 500 µmol/L palmitate compared to control. The level of p-NF-κB p65 protein markedly increased at 60 min post-stimulation and reached a 2.96-fold increase of baseline level at 120 min (P < 0.05) . The IκBα level markedly declined at 60 min post-stimulation and decreased by 57% at 120 min (P < 0.05) . Compared to the group with palmitate treatment alone, pyrrolidine dithiocarbamic acid (10/20 µmol/L) significantly inhibited the palmitate-induced increase of p-NF-κB p65 (1.39 ± 0.12, 1.25 ± 0.10 vs 1.76 ± 0.14, both P < 0.05) , restored the palmitate-induced decrease of caspase-3 (2.24 ± 0.28 vs 1.29 ± 0.27, P < 0.05) and inhibited the palmitate-induced increase of cleaved caspase-3 (0.63 ± 0.01 vs 1.13 ± 0.10, P < 0.05) . CONCLUSION: Palmitate induces apoptosis of MC3T3-E1 cell by an activation of NF-κB.

Comprehensive intensive therapy for Chinese gestational diabetes benefits both newborns and mothers.

OBJECTIVE: This study identified the impact of intensive therapy on neonatal outcomes in women with gestational diabetes mellitus (GDM) and determined the effects on the postpartum metabolic status of the mothers. RESEARCH DESIGN AND METHODS: In total, 127 pregnant women with GDM were randomly selected to receive an intensive treatment regimen, which included one-to-one education, lifestyle intervention, scheduled clinic visits, strict glucose control, and frequent glucose self-monitoring. Meanwhile, 148 age-matched pregnant women with GDM were selected as controls and given the standard treatment regimen. Pregnancy outcomes including parameters related to the GDM mothers and to their neonates were comparatively analyzed between the two treatment groups. GDM patient follow-up (range, 1-3 years after delivery) included an oral glucose tolerance test and measurements of lipid concentration and insulin secretion. The insulinogenic index (ΔInsulin(30 min)/ΔBlood glucose(30 min)) and homeostasis model assessment index of ß-cell function and insulin resistance were calculated. The patients' demographic and anthropometric data were also recorded for comparative analysis. RESULTS: Compared with GDM patients receiving standard treatment, GDM patients receiving intensive treatment had lower instances of premature delivery (2.4% vs. 8.3%, P<0.05) and neonatal care unit admission (21.3% vs. 33.3%, P<0.05) and lower neonatal birth weight (3.26±0.53 vs. 3.45±0.55 kg, P<0.0001). At follow-up, GDM patients from the intensive treatment group had a smaller waist circumference (75.83±3.11 vs. 78.34±4.20 cm, P<0.01), lower 30-min glucose levels after a 75-g glucose load (8.26±1.85 vs. 9.46±2.74 mmol/L, P<0.05), and higher high-density lipoprotein levels (1.30±0.24 vs. 1.18±0.23 mmol/L, P<0.05). CONCLUSIONS: The intensive GDM treatment regimen led to healthier outcomes for the women, the neonates, and the birth event and was associated with better maternal metabolic situations in the months and years after delivery.

Bezafibrate prevents palmitate-induced apoptosis in osteoblastic MC3T3-E1 cells through the NF-κB signaling pathway.

Osteoporosis is a bone condition defined by low bone mass and increase of fracture risk due to imbalance between bone resorption by osteoclasts and bone formation by osteoblasts. Low bone mass is likely to be due to the alteration of the osteoclast and osteoblast lifespan through regulated apoptosis. Saturated fatty acid (SFA) intake is negatively associated with bone mineral density (BMD). Furthermore, SFA induces apoptosis in osteoblastic cell lines. Bezafibrate could increase bone mass in intact male rats principally through increasing periosteal bone formation. At present, it is unknown whether bezafibrate attenuates palmitate-induced apoptosis in MC3T3-E1 cells. In the present study, we found that palmitate stimulated the degradation of IκBα and NF-κB translocation, as well as up-regulation of NF-κB-mediated Fas expression in obsteoblastic MC3T3-E1 cells. Furthermore, the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) could restore palmitate-induced caspase-3 decrease and inhibit palmitate-induced cleaved caspase-3 increase. We observed that bezafibrate, a dual ligand for the peroxisome proliferator-activated receptors α (PPARα) and PPARδ, significantly attenuated the palmitate-induced cytotoxicity as determined by the MTT assay and inhibited the palmitate-induced apoptosis as determined by a flow cytometry assay using Annexin V-FITC/PI and assessment of the activity of caspase-3. Pre-treatment of bezafibrate prevented palmitate-induced NF-κB activation. Therefore, these findings indicate that bezafibrate inbibits palmitate-induced apoptosis via the NF-κB signaling pathway. Our results point to bezafibrate as a new strategy to attenuate bone loss associated with high fat diet beyond its lipid-lowering actions.

Bezafibrate enhances proliferation and differentiation of osteoblastic MC3T3-E1 cells via AMPK and eNOS activation.

AIM: To investigate the effects of bezafibrate on the proliferation and differentiation of osteoblastic MC3T3-E1 cells, and to determine the signaling pathway underlying the effects. METHODS: MC3T3-E1 cells, a mouse osteoblastic cell line, were used. Cell viability and proliferation were examined using MTT assay and colorimetric BrdU incorporation assay, respectively. NO production was evaluated using the Griess reagent. The mRNA expression of ALP, collagen I, osteocalcin, BMP-2, and Runx-2 was measured using real-time PCR. Western blot analysis was used to detect the expression of AMPK and eNOS proteins. RESULTS: Bezafibrate increased the viability and proliferation of MC3T3-E1 cells in a dose- and time-dependent manner. Bezafibrate (100 µmol/L) significantly enhanced osteoblastic mineralization and expression of the differentiation markers ALP, collagen I and osteocalcin. Bezafibrate (100 µmol/L) increased phosphorylation of AMPK and eNOS, which led to an increase of NO production by 4.08-fold, and upregulating BMP-2 and Runx-2 mRNA expression. These effects could be blocked by AMPK inhibitor compound C (5 µmol/L), or the PPARß inhibitor GSK0660 (0.5 µmol/L), but not by the PPARα inhibitor MK886 (10 µmol/L). Furthermore, GSK0660, compound C, or N(G)-nitro-L-arginine methyl ester hydrochloride (L-NAME, 1 mmol/L) could reverse the stimulatory effects of bezafibrate (100 µmol/L) on osteoblast proliferation and differentiation, whereas MK886 only inhibited bezafibrate-induced osteoblast proliferation. CONCLUSION: Bezafibrate stimulates proliferation and differentiation of MC3T3-E1 cells, mainly via a PPARß-dependent mechanism. The drug might be beneficial for osteoporosis by promoting bone formation.

Altered nuclear factor-kappaB inducing kinase expression in insulin-resistant mice.

BACKGROUND: Insulin resistance is an underlying feature of both type 2 diabetes and metabolic syndrome. Currently, it is unclear whether nuclear factor (NF)-κB inducing kinase (NIK) plays a role in the development of insulin resistance. The present in vivo study investigated the roles of NIK and IκB kinase α (IKKα) in obesity-induced insulin resistance using animal models. METHODS: NIK expression was evaluated by Western blotting in male Lep(ob) mice and C57BL/6J mice fed a high-fat diet (HFD) (45% fat). After metformin and sulfasalazine treatment, NIK expression was investigated during the improvement of insulin resistance. RESULTS: NIK was increased by about 1-fold in the renal tissues of Lep(ob) mice and C57BL/6J mice fed a HFD for 12 weeks. After 1 and 3 weeks of high-fat feeding, we observed an almost 50% decrease in NIK and IKKα expression in the liver and renal tissues of C57BL/6J mice. NIK expression was significantly lower in the liver and renal tissues of HFD-fed mice that were treated with insulin sensitizers, metformin and sulfasalazine. However, IKKα expression was increased after metformin treatment in both tissues. CONCLUSION: These results suggest a possible role of NIK in the liver and renal tissues of insulin-resistant mice.

[Three single nucleotide polymorphisms of porphobilinogen deaminase gene related to a Chinese patient with acute intermittent porphyria].

OBJECTIVE: To analyzed the role of genetic factors in pathogenesis of acute intermittent porphyria (AIP). METHODS: Peripheral blood sample was collected from a Chinese female AIP patients, aged 36, to undergo direct sequencing to analyze all the exons and flanking introns of the porphobilinogen deaminase (PBGD) and protoporphyrinogen oxidase (PPOX) genes. The sequencing results were compared with the established human PBGD and PPOX sequences (GenBank Accession No. M95623; NC_000001.9). RESULTS: Direct sequencing showed three kinds of single nucleotide polymorphism (SNP) in the PBGD gene. No mutation was found in the coding regions of either PBGD or PPOX gene. CONCLUSION: The three SNPs may underlie the genetic defects of AIP in Chinese. SNP may serve as genetic markers for linkage analysis to track presymptomatic carriers in AIP families.

Beta-cell dysfunction is the primary contributor to the early postpartum diabetes among Chinese women with history of gestational diabetes mellitus.

BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) are at higher risk of future development of diabetes. This study investigated the risk factors associated with early postpartum abnormal glucose regulation (AGR) among Chinese women with a history of GDM. METHODS: A total of 186 women with a history of GDM were screened for early postpartum AGR at 6-8 weeks after delivery. Those with AGR were given lifestyle intervention therapy and reevaluated in 6-12 months. The demographic, anthropometric, prenatal and delivery data were recorded. The plasma high-sensitivity C-reactive protein (HsCRP) and lipid concentration were measured, and insulin secretion were analyzed. Insulinogenic index Deltains30'/DeltaBG30', the homeostasis model assessment index (HOMA)-B, and HOMA-IR were calculated. Multiple regression analysis was performed to identify the risk factors. RESULTS: Of the GDM women 28.0% (52/186) had AGR at 6-8 weeks after delivery; 45.2% (17/40) of these AGR women reminded abnormal after 6-12 month lifestyle intervention. Compared to the women who reverted to normal, women with consistent AGR showed significantly lower fasting insulin concentration, lower Deltains30'/DeltaBG30' as well as lower HOMA-B. No significant differences in age, body mass index (BMI), waist circumference, blood pressure, lipid level, HsCRP and HOMA-IR were observed between the two groups. Pre-pregnancy BMI = 25 kg/m(2), fasting glucose level = 5.6 mmol/L and/or 75 g oral glucose tolerance test (OGTT) 2 hours glucose level = 11.1 mmol/L during pregnancy were predictors for the AGR at 6-8 weeks after delivery. Deltains30'/DeltaBG30 = 1.05 was a significant risk contributor to the consistent early postpartum AGR. CONCLUSION: There is a high incidence of early postpartum AGR among Chinese woman with prior GDM. Beta-cell dysfunction, rather than insulin resistance or inflammation, is the predominant contributor to the early onset and consistent AGR after delivery.

[Etiological dissection in common anti-islet autoantibody-negative patients with type 1 diabetes].

OBJECTIVE: To explore the immunological and genetic factors of common anti-islet autoantibody-negative patients with type 1 diabetes. METHODS: Specimens of peripheral blood were collected from 33 common autoantibody (GAD-Ab, IA2-Ab, IAA, TGA and TPO-Ab) negative diabetic patients with new-onset of unprovoked ketosis (or ketoacidosis), and genome DNA was extracted. The antibodies to carboxypeptide-H (CPH) and SOX13 (ICA12) were detected by radioligand assay. The gene mutations of MODY3 (HNF-1alpha) and MODY6 (NeuroD1/Beta2) were detected by PCR-SSCP sequencing. Mitochondrial gene mutations were analyzed with PCR-RFLP. RESULTS: Two (6%) of the patients were SOX13-Ab positive, while none of them was positive for CPH-Ab. Gene mutation detection found one case of a new mutation, R321H (CGC-->CAC) in the exon 5 of HNF-1alpha gene and one case with ND1 mt3316 G-->A mutation in mitochondrial DNA. In addition to the diabetes-associated mutations described above, seven polymorphisms of HNF-1alpha gene, including L17L, I27L, L459L, S487N, IVS5 + 9 C > G, IVS6-42 G > T, and IVS7 + 7 G > A, and one NeuroD1/Beta2 gene polymorphic variant Ala45Thr, were found. CONCLUSION: Autoimmunity and gene mutations (such as MODY3 and mitochondrial genes mutations) may be etiological in a few cases initially diagnosed as autoantibody-negative type 1 diabetes. Autoimmunity and MODY and mitochondrial diabetes should be excluded if idiopathic type 1 (type 1B) diabetes is diagnosed.

[Additive effects of the variants in the beta(3)-adrenergic receptor and uncoupling protein-2 genes on obesity in Chinese].

OBJECTIVE: To investigate the additive effects of uncoupling protein 2 (UCP2) gene Ala55Val variation and ADR beta(3) gene Trp64Arg variation on the obesity in Chinese Han population. METHODS: The UCP2 gene Ala55Val variation and ADR beta(3) gene Trp64Arg variation were examined by polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP) in 119 obese subject with mean BMI (27.9+/-2.98)kg/m(2) and in 177 control subjects with mean BMI(21.9+/-1.9)kg/m(2). The additive effects of the two gene mutations were analyzed. RESULTS: (1) The frequency of ADR beta(3) gene Trp64Arg variation in obese subjects was not significantly different from that in control subjects. In control subjects, the Trp64Arg variation carriers had higher fasting glucose level and 2-hour-post-prandial glucose level than did non-carriers. (2) The frequency of homozygote of UCP2 gene Ala55Val variation in obese subjects was higher than that in the control subjects (OR=3.71, P=0.001). In control subjects the Ala55Val variation carriers had higher BMI. (3) When there was only UCP2 gene or ADR beta(3) gene mutation, the frequency of gene mutation in obese subjects was not significantly different from that in control subjects (P>0.05). But when there were simultaneously two gene mutations, the frequency of gene mutations was higher in obese subjects than in control subjects (OR=2.57, P=0.009). (4) The genotype carriers with Val/Val+ Trp/Arg were the greatest relation to obese obesity (OR=8.58, P=0.002). CONCLUSION: The homozygote of UCP2 gene Ala55Val mutation increases the risk of obesity. Though the UCP2 gene mutation alone or the ADR beta(3) gene mutation alone is not associated with obesity, the possible additive effects of the two micro-genes increase the occurring of obesity.

[Common variants in beta 3-adrenergic-receptor and uncoupling protein-2 genes are associated with type 2 diabetes and obesity].

OBJECTIVE: To investigate the effects of uncoupling protein-2 (UCP2) gene Ala55Val variation and beta(3)-adrenergic-receptor (beta(3)-AR) gene Trp64Arg variation on type 2 diabetes and obesity, as well as the combined effects between the two variations. METHODS: The peripheral blood samples of 173 type 2 diabetics, 119 obese persons, and 177 control subjects were collected. PCR-RFLP was used to detect the UCP2 gene Ala55Val variation and beta(3)-AR gene Trp64Arg variation. The haplotype and allele frequency distributions among the three groups were analyzed. The combined effect of the two gene mutations was analyzed too. RESULTS: (1) The frequencies of homozygote of UCP2 gene Ala55Val variation in the diabetes and obesity patients were both significantly higher than that in the control subjects (OR = 4.62, P = 0.001; OR = 3.71, P = 0.001). The Ala55Val variation carriers had higher BMI in the control subjects. (2) The gene frequency of homozygote of beta(3)-AR gene Trp64Arg variation was significantly higher in the diabetes patients than in the control subjects. The Trp64Arg variation carriers had higher fasting and 2-hour postgrandual glucose levels than the non-carriers in the control subjects. (3) When there was only UCP2 gene mutation or beta(3)-AR gene mutation, their frequencies in diabetes and obesity patients were not significantly different from that in the control subjects (both P > 0.05). However, the frequencies of the combined mutations of these two genes in either the diabetes patients or in the obesity patients were both significantly higher than in the control subjects (OR = 3.69, P = 0.000; OR = 2.57, P = 0.009). (4) The Val/Val + Trp/Arg carriers had the greatest relation with diabetes (OR = 10.43, P = 0.000) and obesity (OR = 8.58, P = 0.002). CONCLUSION: The homozygote of UCP2 gene Ala55Val mutation significantly enhances the risks of diabetes and obesity. The homozygote of beta(3)-AR gene Trp64Arg mutation is related with diabetes. The accumulation of the effects of two micro-genes creates obvious phenotypic effects.