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1.  Contribution of SLC30A8 variants to the risk of type 2 diabetes in a multi-ethnic population: a case control study 
Background
Several studies have shown the association of solute carrier family 30 (zinc transporter) member 8 (SLC30A8) rs13266634 with type 2 diabetes (T2D). However, the association of alternative variants and haplotypes of SLC30A8 with T2D have not been studied in different populations. The aim of this study is to assess the association of the alternative SLC30A8 variants, rs7002176 and rs1995222 as well as the most common variant, rs13266634 and haplotypes with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian subjects.
Methods
Single nucleotide polymorphisms (SNPs) of SLC30A8; rs7002176, rs1995222 and rs13266634 were genotyped in 1140 T2D and 973 non-diabetic control subjects. Of these, 33 GADA positive diabetic subjects and 353 metabolic syndrome (MetS) subjects were excluded from subsequent analysis.
Results
The recessive genetic model controlled for age, race, gender and BMI shows that the alternative SLC30A8 variant, rs1995222 is associated with GADA negative diabetes (OR = 1.29, P = 0.02) in Malaysian subjects. The most common variant, rs13266634 is also associated with GADA negative diabetes (OR = 1.45, P = 0.001). This association is more pronounced among Malaysian Indians (OR = 1.93, P = 0.001). Moreover, the CG haplotype and CG-CG diplotype have been equally associated with increased diabetic risk (OR = 1.67, P = 8.6 × 10-5).
Conclusions
SLC30A8 SNPs and haplotypes are associated with GADA negative diabetes in Malaysian subjects, and this association is markedly higher among Malaysian Indian subjects.
doi:10.1186/1472-6823-14-2
PMCID: PMC3893602  PMID: 24393180
T2D; GADA negative diabetes; SLC30A8; Haplotypes; Alternative variants
2.  IGF2BP2 Alternative Variants Associated with Glutamic Acid Decarboxylase Antibodies Negative Diabetes in Malaysian Subjects 
PLoS ONE  2012;7(9):e45573.
Background
The association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) common variants (rs4402960 and rs1470579) with type 2 diabetes (T2D) has been performed in different populations. The aim of this study was to evaluate the association of alternative variants of IGF2BP2; rs6777038, rs16860234 and rs7651090 with glutamic acid decarboxylase antibodies (GADA) negative diabetes in Malaysian Subjects.
Methods/Principal Findings
IGF2BP2; rs6777038, rs16860234 and rs7651090 single nucleotide polymorphisms (SNPs) were genotyped in 1107 GADA negative diabetic patients and 620 control subjects of Asian from Malaysia. The additive genetic model adjusted for age, race, gender and BMI showed that alternative variants; rs6777038, rs16860234 and rs7651090 of IGF2BP2 associated with GADA negative diabetes (OR = 1.21; 1.36; 1.35, P = 0.03; 0.0004; 0.0002, respectively). In addition, the CCG haplotype and diplotype CCG-TCG increased the risk of diabetes (OR = 1.51, P = 0.01; OR = 2.36, P = 0.009, respectively).
Conclusions/Significance
IGF2BP2 alternative variants were associated with GADA negative diabetes. The IGF2BP2 haplotypes and diplotypes increased the risk of diabetes in Malaysian subject.
doi:10.1371/journal.pone.0045573
PMCID: PMC3446917  PMID: 23029108
3.  Plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters in Malaysian subjects 
The plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat insertion/deletion polymorphisms might be genetic determinations of increased or decreased of their plasma activities. The aim of this study was to investigate the association of plasminogen activator inhibitor-1 4G/5G and tissue plasminogen activator Alu-repeat I/D polymorphisms with metabolic syndrome parameters in normal Malaysian subjects and to assess the impact of these polymorphisms on their plasma activities and antigens. The genetic polymorphisms were genotyped in 130 normal subjects. In addition, the plasma activities and antigens of plasminogen activator inhibitor-1 and tissue plasminogen activator as well as levels of insulin, glucose, and lipid profile at fasting state were investigated. The subjects with homozygous 4G/4G showed association with an increased triglyceride (p = 0.007), body mass index (p = 0.01) and diastolic blood pressure (p = 0.03). In addition, the plasminogen activator inhibitor-1 4G/5G polymorphism modulates plasma plasminogen activator inhibitor-1 activity and antigen and tissue plasminogen activator activity (p = 0.002, 0.014, 0.003) respectively. These results showed that, the plasminogen activator inhibitor-1 4G/5G polymorphism is associated with metabolic syndrome parameters, plasminogen activator inhibitor-1 and tissue plasminogen activator activities in Malaysian subjects, and may serve to increase the risk of type 2 diabetes and cardiovascular disease in Malaysian subjects.
doi:10.3164/jcbn.11-48
PMCID: PMC3334369  PMID: 22573918
plasminogen activator inhibitor-1; tissue plasminogen activator; type 2 diabetes; metabolic syndrome; cardiovascular disease
4.  Effect of Plasminogen Activator Inhibitor-1 and Tissue Plasminogen Activator Polymorphisms on Susceptibility to Type 2 Diabetes in Malaysian Subjects 
Elevated activity of plasminogen activator inhibitor-1 (PAI-1) and decreased tissue plasminogen activator (tPA) activity are considered to be important risk factors for type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). The aim of this study was to investigate the association of the PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms with T2DM in Malaysian subjects. Serum insulin, coronary risk panel, plasma glucose, and PAI-1 4G/5G and tPA Alu-repeat I/D polymorphisms were studied in 303 T2DM subjects (227 with MetS and 76 without MetS) and 131 normal subjects without diabetes and MetS. Statistical analysis showed that the dominant and additive models of PAI-1 4G/5G polymorphism showed a weak association with T2DM without MetS (OR = 2.35, P = 0.045; OR = 1.67, P = 0.058). On the other hand, the recessive model of the tPA Alu-repeat I/D polymorphism showed an association with T2DM with MetS (OR = 3.32, P = 0.013) whereas the dominant and additive models of the tPA Alu-repeat I/D polymorphism were not associated with T2DM either with or without MetS.
doi:10.1155/2012/234937
PMCID: PMC3336151  PMID: 22577291
5.  Association of plasminogen activator inhibitor-1 and tissue plasminogen activator with type 2 diabetes and metabolic syndrome in Malaysian subjects 
Background
Increased plasma plasminogen activator inhibitor-1 (PAI-1) activity and decreased tissue plasminogen activator (tPA) activity could be considered a true component of the metabolic syndrome (MetS) associated with an increased risk of developing cardiovascular diseases (CVD) and fibrinolytic abnormalities. The aim of this study was to investigate the association of tPA and its inhibitor PAI-1 with type 2 diabetes (T2D) and MetS and interrelationship between PAI-1and tPA activities and antigens in Malaysian T2D and normal subjects.
Methods
The plasma activities and antigens of PAI-1 and tPA and the levels of the tPA/PAI-1 complex as well as serum insulin, parameter of the coronary risk panel and plasma glucose at fasting state were studied in 303 T2D subjects (227 with MetS and 76 without MetS), 131 normal non-diabetic non-metabolic subjects and 101 non-diabetic MetS subjects.
Results
The PAI-1 activity was higher in subjects with T2D with MetS (P = 9.8 × 10-19) and non-diabetic subjects with MetS (P = 3.0 × 10-15), whereas the tPA activity was lower in T2D with MetS (P = 0.003) as compare to normal subjects. Plasma tPA antigen levels were higher in subjects with T2D with MetS (P = 8.9 × 10-24), T2D without MetS (P = 1.3 × 10-13) and non-diabetic MetS subjects (P = 0.002). The activity and antigen of PAI-1 in normal subjects were related to insulin resistance (P = 2.2 × 10-4; 0.007). Additionally, the PAI-1 activity was associated with an increased waist circumference (P = 2.2 × 10-4) and decreased HDL-c (P = 0.005), whereas the tPA activity was associated with decreased FBG (P = 0.028). The highest correlation was between PAI-1 activity and its antigen (R2 = 0.695, P = 1.1 × 10-36) in diabetic subjects. The tPA activity negatively correlated with its antigen (R2 = -0.444, P = 7.7 × 10-13) in normal subjects and with the PAI-1 activity and antigen (R2 = -0.319, P = 9.9 × 10-12; R2 = -0.228, P = 3.4 × 10-6) in diabetic subjects.
Conclusions
PAI-1 and tPA activities and antigens were associated with diabetes and MetS parameters in Malaysian subjects.
doi:10.1186/1475-2840-10-23
PMCID: PMC3064636  PMID: 21414238
6.  Use of glycated hemoglobin (HbA1C) and impaired glucose tolerance in the screening of undiagnosed diabetes in the Malaysian population 
Although HbA1C is widely accepted as a useful index of mean blood glucose in type 2 diabetic patients its usefulness as screening test for diabetes has been controversial. The present study was undertaken to determine whether the level of HbA1C predicted diabetes in a prediabetic group of subjects. Plasma lipids, oral glucose tolerance, HbA1C was determined in 90 normal control subjects, 57 offspring of one type 2 diabetes mellitus parent and 11 diagnosed type 2 diabetes mellitus individuals. The mean age of participants was 44.5 yrs (not significantly different amongst the three groups) and the mean body mass index was 26.8 (not significantly different amongst the three groups). Two hours after a 75 g glucose challenge, the offspring had a significantly higher plasma glucose level (mean = 7.1 mmol/L, p value = 0.002) than the normals. Similarly the HbA1C values were higher in the offspring than in the normals (mean = 5.78%, p value = 0.016). Besides the significantly higher values for oral glucose tolerance test and HbA1C, the diabetics also were significantly higher for triglycerides (mean = 2.25mmol/L), total cholesterol (mean = 6.24mmol/L) and systolic blood pressure (mean = 138.45mm Hg) than the offspring (P value = 0.031, 0.006, 0.010) and the normals (P value = 0.026, 0.018, 0.002) respectively. The mean values of diastolic blood pressure, LDL cholesterol and HDL cholesterol were not significantly different amongst the three groups.
doi:10.1007/s12291-008-0055-x
PMCID: PMC3453455  PMID: 23105763
Diabetes mellitus; HbA1C; Prediabetic; Fasting blood glucose; Insulin resistance
7.  F2-Isoprostanes as Novel Biomarkers for Type 2 Diabetes: a Review 
Oxidative stress (OS) has been implicated as one of the major underlying mechanisms behind many acute and chronic diseases. However, the measurement of free radicals or their end products is complicated. Isoprostanes, derived from the non-enzymatic peroxidation of arachidonic acid are now considered to be reliable biomarkers of oxidant stress in the human body. Isoprostanes are involved in many of the human diseases such as type 2 diabetes. In type 2 diabetes elevated levels of F2-Isoprostanes (F2-IsoPs) have been observed. The measurement of bioactive F2-IsoPs levels offers a unique noninvasive analytical tool to study the role of free radicals in physiology, oxidative stress-related diseases, and acute or chronic inflammatory conditions. Measurement of oxidative stress by various other methods lacks specificity and sensitivity. This review aims to shed light on the implemention of F2-IsoPs measurement as a gold-standard biomarker of oxidative stress in type 2 diabetics.
doi:10.3164/jcbn.08-266
PMCID: PMC2704321  PMID: 19590700
oxidative stress; lipid peroxidation; isoprostanes; type 2 diabetes
8.  Nε-(Carboxymethyl)lysine and Coronary Atherosclerosis-Associated Low Density Lipoprotein Abnormalities in Type 2 Diabetes: Current Status 
In comparison to the general population, individuals with diabetes suffer a 3- to 4-fold increased risk for developing complications of atherosclerosis and vascular insufficiency. This fact should be taken into account to develop a suitable determinant for the early detection of these complications and subsequently reduce the adverse effect of type 2 diabetes. In vitro experiments have shown that the products of glucose auto-oxidation and Amadori adducts are both potential sources of Nε-(carboxymethyl)lysine (CML). Excessive formation of CML on low density lipoprotein (LDL) has been proposed to be an important mechanism for the dyslipidemia and accelerated atherogenesis observed in patients with type 2 diabetes. It has been postulated that the uptake of CML-LDL by LDL receptors is impaired, thereby decreasing its clearance from the blood circulation. Alternatively, the uptake of these modified LDL particles by scavenger receptors on macrophages and vascular smooth muscle cells (SMCs) and by AGE receptors on endothelial cells, SMCs, and monocytes is highly enhanced and this, in turn, is centrally positioned to contribute to the pathogenesis of diabetic vascular complications especially coronary artery disease. The present review summarizes the up-to-date information on effects and mechanism of type 2 diabetes-associated coronary atherosclerosis induced by CML-LDL modification.
doi:10.3164/jcbn.08-190
PMCID: PMC2613495  PMID: 19177184
Nε-(carboxymethyl)lysine; low density lipoprotein; atherosclerosis; type 2 diabetes
9.  Role of Nε-(Carboxymethyl)Lysine in the Development of Ischemic Heart Disease in Type 2 Diabetes Mellitus 
This study aims to determine the levels of Nε-(carboxymethyl)lysine (CML) in patients with Type 2 diabetic patients with and without ischemic heart disease (IHD) and to find for a possible association between circulating CML and a number of clinical parameters including lipids, hemoglobin A1c (HbA1c) and malondialdehyde (MDA) in Type 2 diabetic IHD patients. Serum CML levels were measured by enzyme-linked immunosorbent assay using polyclonal anti-CML antibodies. Serum levels of CML and MDA were assessed in 60 IHD patients with Type 2 diabetes, 43 IHD patients without Type 2 diabetes, 64 Type 2 diabetics without IHD, and 80 sex- and age-matched healthy subjects. Correlations studies between CML levels and lipids, HbA1c, and lipid peroxidation were performed in Type 2 diabetes patients with and without IHD. A statistical significance was observed in the levels of serum glucose, lipids (triglyceride, total cholesterol, HDL-cholesterol), MDA, HbA1c, CML and LDL-cholesterol (p<0.05) between the groups of the study. CML levels were significantly increased in diabetic IHD patients compared with Type 2 diabetes patients but without IHD (537.1 ± 86.1 vs 449.7 ± 54.9, p<0.001). A positive correlation was observed between serum levels of CML and MDA, r = 0.338 (p = 0.008) in Type 2 diabetes patients with IHD. However, age, HbA1c and lipids had no significant influence on CML levels among diabetics (p>0.05). In conclusion, this study demonstrates the effect of both diabetes and oxidative stress on the higher levels of circulating CML. These results showed that increased serum levels of CML are associated with the development of IHD in Type 2 diabetes mellitus.
doi:10.3164/jcbn.2007014
PMCID: PMC2170948  PMID: 18193103
advanced glycation end products; Nε-(carboxymethyl)lysine; Type 2 diabetes mellitus; ischemic heart disease; oxidative stress

Results 1-9 (9)