[Meta-analysis of the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma gene with type 2 diabetes in Chinese Han population].

OBJECTIVE: To evaluate the association of Pro12Ala polymorphism of peroxisome proliferator activated receptor gamma (PPARgamma) gene with type 2 diabetes (T2DM) in Chinese Han population. METHODS: The present investigation was carried out using the keywords "PPARgamma", "pparg", "Pro12Ala", "type 2 diabetes", and "Chinese. The odds ratios (OR) for Ala12 used as the metric of choice were calculated in the dominant and additive model separately. The Meta-analysis was conducted by software STATA 11.0. RESULTS: (1) We identified 22 studies, of which 17 studies involving 3927 type 2 diabetes cases and 3364 controls fell into the inclusion criteria. The analysis indicated no significant inter-study heterogeneity and publication bias. (2) The frequencies of the minor allele Ala12 in type 2 diabetes and control groups were 4.8% and 4.6% respectively. (3) The combined overall OR of dominant and additive model calculated by fix-effects meta-analysis for type 2 diabetes and the Pro12Ala polymorphism, were 0.95 (95% CI: 0.80, 1.12) and 0.93 (95% CI: 0.79, 1.09) respectively. CONCLUSION: In this meta-analysis, the Pro12Ala gene variant (rs1801282) is not found to be associated with the susceptibility for type 2 diabetes in Chinese Han population.

A Two-Stage Study Identifies Two Novel Polymorphisms in PRKAG2 Affecting Metformin Response in Chinese Type 2 Diabetes Patients.

OBJECTIVE: Individual differences in glycemic response to metformin in antidiabetic treatment exist widely. Although some associated genetic variations have been discovered, they still cannot accurately predict metformin response. In the current study, we set out to investigate novel genetic variants affecting metformin response in Chinese type 2 diabetes (T2D) patients. METHODS: A two-stage study enrolled 500 T2D patients who received metformin, glibenclamide or a combination of both were recruited from 2009 to 2012 in China. Change of HbA1c, adjusted by clinical covariates, was used to evaluate glycemic response to metformin. Selected single nucleotide polymorphisms (SNPs) were genotyped using the Infinium iSelect and/or Illumina GoldenGate genotyping platform. A linear regression model was used to evaluate the association between SNPs and response. RESULTS: A total of 3739 SNPs were screened in Stage 1, of which 50 were associated with drug response. Except for one genetic variant preferred to affect glibenclamide, the remaining SNPs were subsequently verified in Stage 2, and two SNPs were successfully validated. These were PRKAG2 rs2727528 (discovery group: ß=-0.212, P=0.046; validation group: ß=-0.269, P=0.028) and PRKAG2 rs1105842 (discovery group: ß=0.205, P=0.048; validation group: ß=0.273, P=0.025). C allele carriers of rs2727528 and C allele carriers of rs1105842 would have a larger difference of HbA1c level when using metformin. CONCLUSION: Two variants rs2727528 and rs1105842 in PRKAG2, encoding γ2 subunit of AMP-activated protein kinase (AMPK), were found to be associated with metformin response in Chinese T2D patients. These findings may provide some novel information for personalized pharmacotherapy of metformin in China.

Type 1 diabetes induced by immune checkpoint inhibitors.

With the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic ß cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

[Contribution of MODY2 gene to the pathogenesis of Chinese early onset familial type 2 diabetes].

OBJECTIVE: To assess the prevalences of maturity onset diabetes of the young 2 (MODY2) in Chinese early onset familial type 2 diabetic population and explore the possibility of some common DNA variants of MODY2 gene to contribute to the susceptibility of type 2 diabetes in Chinese population. METHODS: A total of 100 early onset type 2 diabetes pedigrees in Beijing were collected. By PCR, all the exons and exon/intron splice sites of MODY2 gene were amplified, and PCR products were sequenced to identify the DNA variants . The SNPs were genotyped by homogenous mass extend (hME) assay in nonjdiabetic control population. RESULTS: Three DNA vatiants in MODY2 gene were identified: one in exon4(ccc-->ccg, heterozygous silent mutation,pro145pro), one in exon7(gcc-->gcg, heterozygous silent mutation, ala233ala), and one in intron 9 (IVS9+8 C>T). The prevalences of these variant alleles were 0.5 in exon 4, 0.5% in exon 7 and 36% in intron 9. An association study was conducted to examine the relationship between the IVS9+8 C>T polymorphism and early onset familial type 2 diabetes, the frequency of allele T of early onset familial type 2 diabetes population was significantly lower, and the frequency of allele C significantly higher, than those of control subjects (P<0.05). CONCLUSION: Our research suggested in Chinese population the prevalences of MODY2 was less than 1% in early onset familial type 2 diabetic patients, the IVS9+8 C>T polymorphism at MODY2 gene, intron 9 or nearby genes was associated with early onset familial type 2 diabetes .

[Cross-sectional study of the pathophysiologic and clinical features in the first-degree relatives of type 2 diabetic patients].

OBJECTIVE: To explore the pathophysiologic and clinical features and investigate the roles of insulin resistance and insulin secretion in the pathogenesis of type 2 diabetes mellitus. METHODS: A total of 888 first-degree relatives without glucose intolerance history underwent an oral glucose test (OGTT) and their level of HbA1c, insulin concentration and lipid levels were determined. The homeostasis model assessment was used to estimate insulin resistance (HOMA(IR)) and beta-cell function (HOMA-beta). The ratio of incremental glucose (DeltaG30) and insulin (DeltaI30) response was used to evaluate the early insulin secretion. DeltaI30/DeltaG30/HOMAIR was used to evaluate the glucose disposition index (DI). RESULTS: In the subjects, 167 were diagnosed with diabetes, 180 with impaired glucose tolerance or/and impaired fasting glucose (impared glucose regulation), 457 with normal glucose tolerance and normal HbA1c, and 84 with normal glucose tolerance and high HbA1c. From normal glucose tolerance through impared glucose regulation to diabetes mellitus, the HOMA(IR), body mass index (BMI), waist/hip ratio (WHR) and serum triglyceride (TG) progressively increased, HOMA-beta cell, DeltaI30/DeltaG30, DI and high density liproprotein (HDL) progressively decreased. Subjects with normal glucose tolerance were divided into three tertile subgroups (1/3, 2/3 and 3/3 groups) with different area under the curve of OGTT glucose, after being adjusted by sex, age, BMI, the 3/3 group was found having higher HOMA(IR), and lower HOMA-beta, DeltaI30/DeltaG30/, and DI than the 1/3 group. CONCLUSION: Both insulin resistance and impaired beta cell function are important pathophysiologic changes contributing to the onset and development of type 2 diabetes. These changes and lipid profile have occurred before a patient is diagnosed with abnormal glucose tolerance.

[Contribution of MODY6 gene in the pathogenesis of familial type 2 diabetes in Chinese population].

OBJECTIVE: To investigate the contribution of MODY6 gene in the pathogenesis of familiar type 2 diabetes in Chinese population. METHODS: PCR and single strand configuration polymorphism (PCR-SSCP) technique was used to screen the coding sequence of NeuroD1/BETA2 gene for DNA variants in 188 probands in the pedigrees of familiar type 2 diabetes and 130 normal persons as controls in Beijing, China. The discovered variants were confirmed by sequencing. RESULTS: A4T5 polymorphism and a novel Gly12Arg mutation were found. The frequency of A4T5 of the patients was 19.7%, significantly higher than that of the controls (10.0%, P < 0.05). In the control group, the Homa-beta of the 13 subjects with T allele was 4.6 +/- 04, significantly lower than that of the 117 subjects without T allele (4.9 +/- 0.5, P < 0.05). Co-segregating with diabetes, Gly12Arg mutation was found in only one pedigree and in none normal subjects. CONCLUSION: A4T5 polymorphism of NeuroD1/BETA2 gene is correlated with familiar type 2 diabetes in Chinese population. NeuroD1/BETA2 gene or its nearby gene may play a role in the pathogenesis of familiar type 2 diabetes. The novel GlyArg mutation may be a genetic cause of some diabetic pedigrees.

Relationship Between Serum Zinc Level and Microvascular Complications in Patients with Type 2 Diabetes.

BACKGROUND: Previous studies suggested that zinc level was related to a certain diabetic microvascular complication. However, the relationship between zinc level and all the microvascular complications in type 2 diabetic patients remains unknown. The purpose of this study was to analyze the relationship between zinc level and each diabetic microvascular complication and identify the features related to low serum zinc level. METHODS: We included the hospitalized patients with type 2 diabetes (T2D) at our department from May 30, 2013 to March 31, 2014. We initially compared the serum zinc levels between patients with specific microvascular complications and those without. We then analyzed the association between zinc level and each microvascular complication. Furthermore, we identified the unique features of patients with high and low serum zinc levels and analyzed the risk factors related to low zinc level. RESULTS: The 412 patients included 271 with microvascular complications and 141 without any microvascular complications. Serum zinc level was significantly lower in patients with diabetic retinopathy (P < 0.001), diabetic nephropathy (DN, P < 0.001), or diabetic peripheral neuropathy (P = 0.002) compared with patients without that specific complication. Lower zinc level was an independent risk factor for DN (odds ratio = 0.869, 95% confidence interval = 0.765-0.987, P < 0.05). The subjects with lower serum zinc level had manifested a longer duration of diabetes, higher level of hemoglobin A1c, higher prevalence of hypertension and microvascular complications, and lower fasting and 2-h C-peptide levels. CONCLUSIONS: Lower serum zinc level in T2D patients was related to higher prevalence of diabetic microvascular complications, and represented as an independent risk factor for DN. Patients with lower zinc level were more likely to have a longer duration of diabetes, poorer glucose control, and worse ß-cell function.

IL-1B rs1143623 and EEF1A1P11-RPL7P9 rs10783050 polymorphisms affect the glucose-lowing efficacy of metformin in Chinese overweight or obese Type 2 diabetes mellitus patients.

AIM: To investigate the potential genetic effect on metformin efficacy in overweight or obese Chinese Type 2 diabetes mellitus (T2DM) patients. PATIENTS & METHODS: 768 SNPs in or close to 207 genes were genotyped in 84 patients treated with metformin + glibenclamide/Xiaoke Pill. Significant SNPs were then verified in 107 recent-onset overweight or obese T2DM patients treated with metformin alone. Genotyping was done by Illumina GoldenGate Assay. RESULTS: In the discovery stage, 22 SNPs were nominally significant. IL1B rs1143623 (p = 0.011) and EEF1A1P11-RPL7P9 rs10783050 (p = 0.021) were still significantly associated with the relative change of HbA1c in the replication stage. CONCLUSION: IL1B rs1143623 and EEF1A1P11-RPL7P9 rs10783050 polymorphisms may contribute to metformin's glucose-lowing efficacy in overweight or obese Chinese T2DM patients.

[Study on Calpain10 gene polymorphism in Chinese type 2 diabetes families].

OBJECTIVE: To detect the Calpain10 gene polymorphisms in North China families with type 2 diabetes and to investigate their association with type 2 diabetes. METHODS: PCR-RFLP method was used to test the polymorphisms of Calpain10 SNP43 (G/A) and SNP19 (1/2) in 801 individuals from 218 type 2 diabetes mellitus (DM) families, 211 type 2 diabetes patients without family history, and 127 normal control subjects in northern China. RESULTS: (1) The Calpain 10 SNP43 "G" allele frequency was 91.9% in the type 2 diabetic patients without family history, 92.7% in the probands from the type 2 diabetes families without linkage between the onset of DM and SNP43 site, and 95.3% in the probands from type 2 diabetes families with linkage evidence at SNP43, all significantly higher than that in the controls (85.8%, chi(2) = 6.39, df = 1,P = 0.011; chi(2) = 8.437,df = 1, P < 0.01); and chi(2) = 16.49, df = 1, P < 0.01). The distribution of polymorphism of the SNP19 site was not significantly different between the patients and control subjects. (2) Logistic regression analysis adjusted by BMI, sex and age showed that SNP43 G/G genotype was associated with type 2 diabetes. The odds ratios of the three group were OR = 1.78, P = 0.045; OR = 2.53, P = 0.008; OR = 4.32, P = 0.000 respectively. CONCLUSION: SNP43 site of Calpain10 gene is related to type 2 diabetes. Calpain 10 gene may be a related gene of type 2 diabetes in Chinese.

[Insulin sensitivity and beta function in the first-degree relatives of type 2 diabetic patients].

OBJECTIVE: To investigate the roles of insulin resistance and beta-cell function in the pathogenesis of type 2 diabetes mellitus. METHODS: 614 first-degree relatives without glucose intolerance history underwent an oral glucose test (OGTT) and their levels of HbA1c were determined. According to the single OGTT results and WHO criteria, 118 (19.2%) of the 614 subjects were newly diagnosed with diabetes, 121 (19.7%) with impaired glucose tolerance (IGT) or/and impaired fasting glucose (IFG), 375 with normal glucose tolerance (NGT), of which 316 (51.5%) subjects were with HbA1c in normal level range (4% approximately 6%) and the others with high HbA1c level (9.6%). Homeostasis model assessment of insulin resistance (Homa(IR)) was used to estimate insulin resistance, Homa-beta cell was used to evaluate basal insulin secretion, incremental glucose (DeltaG30) and insulin (DeltaI30) response was calculated as the difference between the values 30 min after glucose intake to evaluate the early insulin secretion, DeltaI30/DeltaG30/HOMA(IR) was used to evaluate the disposition index (DI). RESULTS: Decreasing glucose tolerance was associated with insulin resistance, beta cell function and DI. From normal glucose tolerance condition through IFG /IGT to diabetic, the Homa IR progressively increased (NGT 0.76 +/- 0.6, IFG/IGT 1.0 +/- 0.6, DM 1.5 +/- 0.6, P < 0.001), Homa-beta cell (NGT 5.3 +/- 0.7, IFG/IGT 5.1 +/- 0.7, DM 4.1 +/- 0.9), I30/DeltaG30 (NGT 2.8 +/- 0.9, IFG/IGT 2.2 +/- 1.0, DM 1.3 +/- 1.0) and DI (NGT 2.0 +/- 0.9, IFG/IGT 1.1 +/- 0.9, DM -0.2 +/- 1.2), progressively decreased (P < 0.001). Normal subjects were divided into three tertile groups with different area under the curve of OGTT glucose. After adjusted by sex, age, BMI and WHR, the upper terile group was found having high Homa IR and lower Homa-beta, DeltaI30/DeltaG30/, I than lower tertile group. CONCLUSION: Abnormal glucose tolerance is common in first-degree relatives of non-insulin-dependent Diabetes Mellitus patients, both insulin resistance and impaired beta cell function are associated with impaired glucose metabolism, which have existed before diagnosis of IFG, IGT and diabetes.

Efficacy and safety of insulin treatment in type 2 diabetes using a new index called glucose safety control index.

OBJECTIVE: To recommend an index named glucose safety control index (GSCI) to evaluate the efficacy and safety for insulin regimens. DATA SOURCES: We searched databases for primary studies published in English. The main search concepts were type 2 diabetes, insulin treatment, premixed insulin, premixed insulin analogs, basal inuslin, basal inuslin analogs, bolus insulin, bolus insulin analogs, safety and efficacy. STUDY SELECTION: Studies were eligible for inclusion if they met all of the following criteria: (1) type 2 diabetic patients aged >18 years were included; (2) random control studies with at least 12 weeks of follow-up; (3) different insulin regimens were evaluated. RESULTS: When long-acting basal insulin therapy compared with neutral protamine Hagedorn (NPH) insulin therapy, the proportion of GSCI%A1c ratio more than 1 was 100%, the proportion of GSCIΔA1c ratio more than 1 was 94.44%. When premixed insulin therapy compared with oral hypoglycemic agents plus basal insulin therapy, the proportion of GSCI%A1c ratio more than 1 was 45.5%, the proportion of GSCIΔA1c ratio more than 1 was 38.9%. When premixed insulin therapy compared with oral hypoglycemic agents, the proportion of GSCI%A1c ratio less than 1 was 100%, the proportion of GSCIΔA1c ratio more than 1 was 50%. When premixed insulin therapy compared with basal-bolus insulin therapy, the proportion of GSCI%A1c ratio more than 1 was 37.5%, the proportion of GSCIΔA1c ratio more than 1 was 50%. CONCLUSION: According to the GSCI ratio, long-acting basal insulin therapy tended to be superior to NPH therapy, oral hypoglycemic agents plus basal insulin therapy tended to be superior to premixed insulin therapy, noninsulin antidiabetic agents and premixed insulin therapy was comparable, and basal-bolus insulin therapy tended to be superior to premixed insulin therapy in type 2 diabetes.

Replication of association study between type 2 diabetes mellitus and IGF2BP2 in Han Chinese population.

BACKGROUND: The association between IGF2BP2 and type 2 diabetes mellitus (T2DM) has been repeatedly confirmed among different ethnic populations. However, in several genome-wide association studies (GWAS) from the Chinese Han population, the gene IGF2BP2 has not been replicated. The results of relevant studies for the association between IGF2BP2 and T2DM showed controversy in Chinese Han population. It is necessary to systematically evaluate the contribution of common variants in IGF2BP2 to T2DM in Chinese Han population. METHODS: Two single-nucleotide polymorphisms (SNPs, rs4402960 and rs1470579) in IGF2BP2 were genotyped in Chinese Han population (3807 controls/4531 T2DM cases) by Illumina GoldenGate Indexing assay. The association between SNPs and T2DM was evaluated by multiple Logistic Regression analysis. A meta-analysis was used to estimate the effects of IGF2BP2 in 20854 Chinese Han individuals. RESULTS: rs1470579 and rs4402960 were confirmed to have strong association with T2DM in the Chinese Han population (rs1470579 P = 1.80×10(-7), OR (95% CI) = 1.22 (1.14-1.32), rs4402960 P = 7.46×10(-9), OR (95% CI) = 1.26 (1.17-1.37), respectively). Moreover, 11 studies for rs4402960 were included in the meta-analysis and 7 studies for rs1470579. The meta-analysis also showed the association between T2DM and IGF2BP2 (rs1470579 OR of 1.15 (95% CI = 1.10-1.19), P < 0.0001 under an additive model and rs4402960 OR of 1.14 (95% CI = 1.10-1.18), P < 0.0001 under an additive model). CONCLUSION: IGF2BP2 was strongly associated with the risk of T2DM in Chinese Han population.

High-normal serum uric acid is associated with albuminuria and impaired glomerular filtration rate in Chinese type 2 diabetic patients.

BACKGROUND: Recently, some studies had shown that elevated serum uric acid (SUA) itself may increase the risk for development of renal disease in patients with diabetes. This study aimed to explore whether SUA was a predictor of microalbuminuria and impaired renal function in type 2 diabetes in Chinese patients. METHODS: This cross-sectional study included 2108 type 2 diabetic patients. Kidney function was estimated using the simplified modification of diet in renal disease (MDRD) equation to obtain estimated glomerular filtration rate. The urine samples were obtained for measuring the albumin-to-creatinine ratio (ACR). RESULTS: According to the ACR level, these patients were divided into two groups, normal ACR (NA) and non-normal ACR (non-NA). Both SUA and creatinine were significantly higher in the non-NA group than those in the NA group ((318.89 ± 107.52) vs. (283.44 ± 88.64) µmol/L, and (95.08 ± 53.24) vs. (79.63 ± 18.20) µmol/L, respectively). Logistic regression analysis showed that diabetic duration, systolic blood pressure, creatinine and SUA were the independent predictors of albuminuria. Furthermore, to identify the factors associated with renal function, these patients were divided into two groups according to the MDRD level (MDRD < 90 or MDRD ≥ 90). Both SUA and creatinine were significantly higher in the lower MDRD group than those in the higher MDRD group ((301.90 ± 96.46) vs. (264.07 ± 84.74) µmol/L, and (89.10 ± 31.00) vs. (66.37 ± 11.15) µmol/L, respectively). Logistic regression analysis showed that only age and SUA were the independent predictors of MDRD. CONCLUSION: High-normal SUA was associated with albuminuria and impaired glomerular filtration rate in Chinese type 2 diabetic patients.

Contribution of the Akt2 gene to type 2 diabetes in the Chinese Han population.

BACKGROUND: The Akt2 protein kinase is thought to be a key mediator of the insulin signal transduction process. Akt2 is suggested to play a role in glucose metabolism and the development or maintenance of proper adipose tissue and islet mass. In order to determine whether the Akt2 gene plays a role in the pathogenesis of type 2 diabetes characterized by insulin resistance, and to further identify if variations in this gene have a relationship with type 2 diabetes, we sequenced the entire coding region and splice junctions of Akt2 and made a further case-control study to explore the association between single-nucleotide polymorphisms (SNPs) in this gene and type 2 diabetes in the Chinese Han population. METHODS: We selected 23 probands with a type 2 diabetic pedigree whose family members' average onset age was within 25 to 45 years old. The body mass index of all the participants was lower than 28 kg/m(2) and all of them were insulin-resistant (the fasting insulin level > 100 pmol/L or 16 µIU/ml). The entire coding region and splice junctions of Akt2 were directly sequenced in these 23 probands. SNPs with a frequency of minor allele over 20 percent were selected to be further studied in a case-control study. We chose 743 non-diabetic subjects as the control group and 742 type 2 diabetic patients as the case group. All these subjects were genotyped. A Snapshot Technology Platform (Applied Biosystems) was used for genotyping. RESULTS: The Akt2 genes from all 23 subjects were successfully sequenced. We did not identify any mutation in the type 2 diabetic pedigree. Two SNPs were identified, 13010323T > C and 13007939G > T. 13010323T > C was in intron 9, which was the location of rs2304188 reported in Genbank. Its minor allele frequency was 13.04%. 13007939G > T was in the 3'-untranslated region (UTR) of exon 14, which was the location of rs2304186 reported in Genbank. Its minor allele frequency was 34.78%. The allele frequency of rs2304188 and rs2304186 were consistent with the frequency reported in Genbank. In the case-control study with 742 patients and 743 controls, there was no significant difference between the two groups for the allele frequency of rs2304186 (odd ratio: 0.96, 95% confidence interval: 0.82 - 1.12, P = 0.597). CONCLUSIONS: The Akt2 gene is not a major cause of diabetes in a non-obese Chinese Han population characterized by insulin resistance. There is no significant relationship between rs2304186 and type 2 diabetes in the Chinese Han population.

Association between serum uric acid and different states of glucose metabolism and glomerular filtration rate.

BACKGROUND: Recently, it has been suggested that the serum uric acid (SUA) level decreased in diabetic patients. The aim of this study was to explore the association between SUA level and different state of glucose metabolism and glomerular filtration rate (GFR) reflected by the simplified Modification of Diet in Renal Disease (MDRD) equation and to test the hypothesis that high MDRD is one of the determinants of SUA level. METHODS: This cross-sectional study included 2373 subjects in Beijing who underwent a 75 g oral glucose tolerance test (OGTT) for screening of diabetes. According to the states of glucose metabolism, they were divided into normal glucose tolerance, impaired glucose regulation and diabetes. RESULTS: Multiple stepwise linear regression analysis showed that adjusted by gender, SUA was positively correlated with body mass index (BMI), waist/hippo ratio, systolic blood pressure (SBP) and triglyceride, meanwhile negatively correlated with age, hemoglobin A1c, fasting insulin and MDRD. There was an increasing trend in SUA concentration and a decreasing trend in MDRD when the levels of fasting plasma glucose (FPG) increased from low to high up to the FPG level of 8.0 mmol/L; thereafter, the SUA concentration started to decrease with further increases in FPG levels, and the MDRD started to increase with further increases in FPG levels. CONCLUSION: This study confirmed the previous finding that SUA decreased in diabetes and provided the supporting evidence that the increased MDRD might contribute to the fall of SUA.

Effect of genetic variants in KCNJ11, ABCC8, PPARG and HNF4A loci on the susceptibility of type 2 diabetes in Chinese Han population.

BACKGROUND: KCNJ11, ABCC8, PPARG, and HNF4A have been found to be associated with type 2 diabetes in populations with different genetic backgrounds. The aim of this study was to test, in a Chinese Han population from Beijing, whether the genetic variants in these four genes were associated with genetic predisposition to type 2 diabetes. METHODS: We studied the association of four representative SNPs in KCNJ11, ABCC8, PPARG, and HNF4A by genotyping them using ABI SNaPshot Multiplex System in 400 unrelated type 2 diabetic patients and 400 unrelated normoglycaemic subjects. RESULTS: rs5219 (E23K) in KCNJ11 was associated with genetic susceptibility to type 2 diabetes (OR = 1.400 with 95% CI 1.117 1.755, P = 0.004 under an additive model, OR = 1.652 with 95% CI 1.086 2.513, P = 0.019 under a recessive model, and OR = 1.521 with 95% CI 1.089 2.123, P = 0.014 under a dominant model) after adjusting for sex and body mass index (BMI). We did not find evidence of association for ABCC8 rs1799854, PPARG rs1801282 (Pro12Ala) and HNF4A rs2144908. Genotype-phenotype correlation analysis revealed that rs1799854 in ABCC8 was associated with 2-hour postprandial insulin secretion (P = 0.005) after adjusting for sex, age and BMI. Although no interactions between the four variants on the risk of type 2 diabetes were detected, the multiplicative interaction between PPARG Pro12Ala and HNF4A rs2144908 was found to be associated with 2-hour postprandial insulin (P = 0.004 under an additive model for rs2144908; and P = 0.001 under a dominant model for rs2144908) after adjusting for age, sex and BMI, assuming a dominant model for PPARG Pro12Ala. CONCLUSIONS: Our study replicated the association of rs5219 in KCNJ11 with type 2 diabetes in Chinese Han population in Beijing. And we also observed that ABCC8 as well as the interaction between PPARG and HNF4A may contribute to post-challenge insulin secretion.

[Molecular scanning of MODY1 gene mutations in pedigrees of early onset type 2 diabetes in Beijing].

OBJECTIVE: To explore MDOY1 gene mutations in pedigrees of early-onset familial type 2 diabetes. METHODS: We collected 100 early-onset type 2 diabetes pedigrees in Beijing, in which the probands were diagnosed with type 2 diabetes before the age of 40 years with at least one first-degree relative having such a diagnosis before the age of 45 years. PCR was employed to amplify all the exons and exon/intron splice sites of MDOY1 gene and the PCR products were sequenced to identify the DNA variants. RESULTS: Two DNA variants in the noncoding region including IVS1C +44A>T and IVS2 -5C>T were identified, and 3 mutations in the coding region we identified M49V, T130I, and S462S were found in these pedigrees. CONCLUSION: Currently no sufficient evidence has been obtained to identify the variation in or near MDOY1 genes as the major cause of early-onset type 2 diabetic in Chinese population.