Adiponectin gene variants and the risk of coronary artery disease in patients with type 2 diabetes

Patients with type 2 diabetes (T2D) are more susceptible to develop cardiovascular complications than non-diabetic subjects. Several studies have indicated a role of adiponectin gene in the increased coronary artery disease (CAD) risk in T2D patients. The data however is limited and have been inconsistent. In this study we examined the association of SNP45T>G and SNP276G>T of adiponectin gene with CAD risk in T2D patients in a Saudi population. A total of 418 type 2 diabetic patients were randomly recruited in this study from the RIYADH COHORT. Of the total diabetes patients, 123 were also diagnosed to have CAD, while the rest were control subjects. Anthropometric, clinical and biochemical parameters were measured by standard procedures. Genotyping of polymorphisms was carried out by PCR–RFLP analysis. Genotype distribution of SNP45T>G was significantly (P = 0.005) different between control and CAD subjects, while the distribution of SNP276G>T genotypes was comparable between the subjects. The SNP45T>G was significantly associated with risk of CAD [OR (95% CI), 4.7 (1.6–13.5), P < 0.003] but not SNP276G>T [OR (95% CI), 1.02 (0.53–1.9), P > 0.05]. The association of SNP45T>G with CAD risk remained significant even after adjusting for potential confounding factors [OR (95% CI), 7.2 (1.1–45.9), P < 0.05]. The SNP45T>G of adiponectin gene is an independent risk factor for CAD in T2D patients in a Saudi population. These findings support a role for adiponectin gene in the increased CAD risk in diabetes patients and are consistent with genetic heterogeneity in the association between adiponectin gene and coronary artery disease.     

Postprandial metabolite profiles associated with type 2 diabetes clearly stratify individuals with impaired fasting glucose

Introduction

Fasting metabolite profiles have been shown to distinguish type 2 diabetes (T2D) patients from normal glucose tolerance (NGT) individuals.

Objectives

We investigated whether, besides fasting metabolite profiles, postprandial metabolite profiles associated with T2D can stratify individuals with impaired fasting glucose (IFG) by their similarities to T2D.

Methods

Three groups of individuals (age 45–65 years) without any history of IFG or T2D were selected from the Netherlands Epidemiology of Obesity study and stratified by baseline fasting glucose concentrations (NGT (n?=?176), IFG (n?=?186), T2D (n?=?171)). 163 metabolites were measured under fasting and postprandial states (150 min after a meal challenge). Metabolite profiles specific for a high risk of T2D were identified by LASSO regression for fasting and postprandial states. The selected profiles were utilised to stratify IFG group into high (T2D probability?≥?0.7) and low (T2D probability?≤?0.5) risk subgroups. The stratification performances were compared with clinically relevant metabolic traits.

Results

Two metabolite profiles specific for T2D (n_fasting = 12 metabolites, n_postprandial = 4 metabolites) were identified, with all four postprandial metabolites also being identified in the fasting state. Stratified by the postprandial profile, the high-risk subgroup of IFG individuals (n?=?72) showed similar glucose concentrations to the low-risk subgroup (n?=?57), yet a higher BMI (difference: 3.3 kg/m² (95% CI 1.7–5.0)) and postprandial insulin concentrations (21.5 mU/L (95% CI 1.8–41.2)).

Conclusion

Postprandial metabolites identified T2D patients as good as fasting metabolites and exhibited enhanced signals for IFG stratification, which offers a proof of concept that metabolomics research should not focus on the fasting state alone.

     

Adipokine pattern in subjects with impaired fasting glucose and impaired glucose tolerance in comparison to normal glucose tolerance and diabetes

Aim

Altered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.

Methods

Based on 75 g oral glucose tolerance tests, 124 individuals were divided into groups of IFG (n = 35), IGT (n = 45), or NGT (n = 43). Furthermore, 56 subjects with T2D were included. Serum concentrations of adiponectin, chemerin, fetuin-A, leptin, interleukin (IL)-6, retinol-binding protein 4 (RBP4), monocyte chemoattractant protein (MCP)-1, vaspin, progranulin, and soluble leptin receptor (sOBR) were measured by ELISAs.

Results

Chemerin, progranulin, fetuin-A, and RBP4, IL-6, adiponectin and leptin serum concentrations were differentially regulated among the four investigated groups but only circulating chemerin was significantly different in patients with IGT compared to those with IFG. Compared to T2D the IFG subjects had higher serum chemerin, progranulin, fetuin-A and RBP4 levels which was not detectable in the comparison of the T2D and IGT group.

Conclusion

Alterations in adipokine serum concentrations are already detectable in prediabetic states, mainly for chemerin, and may reflect adipose tissue dysfunction as an early pathogenetic event in T2D development. In addition, distinct adipokine serum patterns in individuals with IFG and IGT suggest a specific role of adipose tissue in the pathogenesis of these prediabetic states.     

Development of impaired glucose tolerance and diabetes in follow-up offspring of Caribbean patients with type 2 diabetes: analysis of 5-year follow-up study

Several reports agreed that the antecedent markers for developing diabetes in offspring of type 2 diabetic patients involve excess body weight and insulin resistance. This study examined the pattern of changes in anthropometric and biochemical risk factors for developing diabetes in a follow-up offspring of Caribbean type 2 diabetic patients. Results of 46 offspring of type 2 diabetic patients who had received one-to-one individualized diet and exercise counseling for 5 years in our laboratory were analyzed. Changes in anthropometric (body weight, waist circumference) and biochemical (insulin, glucose, lipids, HOMA-insulin resistance, HOMA-percent beta-cell function) parameters over the 5-year period were analyzed using ANOVA tests. Of the 46 offspring, 10.9 and 2.2%, respectively, developed impaired glucose tolerance (IGT) and diabetes. Over the years, IGT offspring had a significant step-wise increase and decrease in fasting and 2-h postprandial plasma glucose levels (P < 0.05) and percent B-cell function (P < 0.001), respectively. Again, a non-significant step-wise increase was observed in body mass index, waist circumference and HOMA-insulin resistance levels (P > 0.05). While we await the results of medication-based intervention studies in different populations, exercise and diet counseling will remain the only available lifestyle intervention strategy for slowing IGT progression to diabetes.     

Diet-induced impaired glucose tolerance and gestational diabetes in the dog

Glucose metabolism was compared in dogs consuming a chow/meat diet throughout pregnancy (P group, n = 6) and dogs switched to a high-fat/high-fructose (HFF) diet during the 4th-5th gestational week (gestation ?9 wk; P-HFF group; n = 6). An oral glucose tolerance test (OGTT; 0.9 g/kg) was administered in the 6th-7th gestational week, and a hyperinsulinemic [0-120 min: 1.8 pmol·kg(-1)·min(-1) (low insulin); 120-240 min: 9 pmol·kg(-1)·min(-1) (high insulin)] euglycemic clamp was performed the following week. Nonpregnant (NP) female dogs underwent OGTTs but not clamp studies. All P-HFF dogs exhibited impaired glucose tolerance (IGT) or gestational diabetes (GDM), but only one P dog had IGT. Insulin concentrations in P and P-HFF dogs were significantly lower than in NP dogs 30 and 60 min after the OGTT. Therefore, mean islet size and area were evaluated in P and NP dogs. These values did not differ between groups, and proliferating endocrine cells were rare in pregnancy. During exposure to high insulin, glucose infusion rate and hindlimb glucose uptake were ～30% greater (P < 0.05) and net hepatic glucose output was more suppressed (-5.5 ± 6.1 vs. 7.8 ± 2.8 mg·100 g liver(-1)·min(-1), P < 0.05) in P than in P-HFF dogs. In conclusion, in the 2nd trimester the canine pancreas does not exhibit islet hypertrophy, hyperplasia, or neogenesis. Combined with the lack of pancreatic adaptation, a HFF diet during late pregnancy produces a canine model of IGT and GDM without hyperinsulinemia but exhibiting liver and muscle insulin resistance.     

Functional variants in the lipoprotein lipase gene and risk cardiovascular disease.

The current report is a quantitative review of the relationship between lipoprotein lipase gene variants and cardiovascular disease based on published population-based studies. Sixteen studies, representing 17,630 individuals, report allelic distribution for lipoprotein lipase gene variants among patients and control individuals. Patient outcomes included clinical cardiovascular disease events, documented coronary disease based on angiography, or intimal media thickening by B-mode ultrasonography. Mantel-Haenszel stratified analysis was used to compute a summary odds ratio and 95% confidence intervals for the association between rare allele in the lipoprotein lipase gene and disease status. Because of potential differing effects associated with different lipoprotein lipase variants, each lipoprotein lipase mutant allele was considered separately. The lipoprotein lipase D9N/-93G to T allele has a summary odds ratio of 2.03 (95% confidence interval 1.30-3.18), indicating a twofold increase in risk of coronary disease for carriers with this allelic variant. The summary odds ratio for the relationship of the rare lipoprotein lipase G188E variant with cardiovascular disease is 5.25 (95% confidence interval 1.54-24.29). The lipoprotein lipase N291S allele is associated with a marginal increase in cardiovascular disease (summary odds ratio 1.25, 95% confidence interval 0.99-1.60, P = 0.07). However, there is stronger evidence for a positive association in certain populations. The summary odds ratio for lipoprotein lipase S447X allele is 0.81 (95% confidence interval 0.65-1.0), which indicates a cardioprotective effect of this lipoprotein lipase gene variant. Thus, lipoprotein lipase gene variants are associated with differential susceptibility to cardiovascular disease.     

A simplified Finnish diabetes risk score to predict type 2 diabetes risk and disease evolution in a German population.

AIMS: The FINDRISC questionnaire is a screening tool to estimate the risks for type 2 diabetes as well as asymptomatic type 2 diabetes. We aimed to evaluate its performance to predict diabetes in a German population and to compare its predictive and detective ability in the same population. METHODS: A total of 552 subjects with increased risk of type 2 diabetes were investigated. All individuals completed the FINDRISC questionnaires and underwent an oral glucose tolerance test (OGTT). All individuals were followed for 3 years and underwent an OGTT again. The performance of the opportunistic screening was assessed with the area under the receiver operating characteristics curve (AUC). An intervention program was carried out for all diabetic and IFG/IGT patients at baseline. RESULTS: For identification, the asymptomatic type 2 DM was named Condition 1; prediction of type 2 DM risk in the follow-up survey as Condition 2; and diabetes risk predicting in a hypothetical case of survey without intervention program as Condition 3. The ROC-AUC in the three condition were AUC (FINDRISC1)=0.745, AUC (FINDRISC2)=0.789, and AUC (FINDRISC3)=0.775, respectively. A significant association between FINDRISC and evolution of disease was found, but the variation of plasma glucose during the three years follow-up was not associated with FINDRISC. People in the intervention group with an improvement of glucose tolerance had a smaller FINDRISC score than persons with an unchanged or progressive condition of disease. CONCLUSION: FINDRISC was validated in our study as a simple tool with high performance to predict diabetes risk and less efficient to identify asymptomatic type 2 diabetes. People with lower FINDRISC score will benefit easier from preventive intervention.     

Gender differences in adiponectin and low-grade inflammation among individuals with normal glucose tolerance,prediabetes, and type 2 diabetes

Background: Women with prediabetes and type 2 diabetes mellitus have a higher relative risk of cardiovascular disease than do men. The reason for this is unknown.Objective: We studied the gender differences in adiponectin and in low-grade inflammation, measured by high-sensitivity C-reactive protein (hs-CRP) and interleukin-1 receptor antagonist (IL-1RA), in individuals with normal glucose tolerance, prediabetes, and type 2 diabetes.Methods: In this population-based, cross-sectional study, all individuals born in 1942, 1947, 1952, 1957, and 1962 in Pieksämäki, East Finland, were recruited for participation. A 75-g oral glucose tolerance test and lipid panel were performed, and concentrations of adiponectin, hs-CRP, and IL-1RA were measured. The World Health Organization diagnostic criteria for diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were used. Statistical comparisons between men and women were performed by a bootstrap-type ANCOVA.Results: The eligible population included 1294 middle-aged individuals, and of these, 904 (406 men and 498 women) had complete data and were included in the analyses. Absolute adiponectin concentrations were significantly higher in women at all levels of glucose tolerance (normal, prediabetes, and type 2 diabetes), but the gender ratio (women to men) for adiponectin concentrations decreased linearly (P = 0.011) from normal glucose tolerance (1.61; 95% CI, 1.48–1.75) to prediabetes (1.57; 95% CI, 1.36–1.83) and diabetes (1.16; 95% CI, 0.87–1.53). Among participants with normal glucose tolerance, no significant difference was found between the sexes in hs-CRP or IL-1RA. Among patients with prediabetes or diabetes, women had significantly higher concentrations than did men for hs-CRP (for prediabetes, 2.0 vs 1.5 mg/L; ratio, 1.39; 95% CI, 1.04–1.85) and IL-1RA (for prediabetes, 255 vs 178 pg/mL; ratio, 1.43; 95% CI, 1.121.83). The gender ratios (women to men) increased linearly from normal glucose tolerance to prediabetes and type 2 diabetes for both hs-CRP (P = 0.019) and IL-1RA (P = 0.013).Conclusions: Adiponectin concentrations in women decreased relatively more compared with men across individuals with normal glucose tolerance, prediabetes, and type 2 diabetes, whereas inflammatory markers increased relatively more in women. Higher inflammatory stress in women than in men with prediabetes and type 2 diabetes may explain their relatively higher cardiovascular disease risk.     

Association between osteoprotegerin gene polymorphisms and cardiovascular disease in type 2 diabetic patients

Osteoprotegerin (OPG) gene polymorphisms (T245G, T950C and G1181C) have been associated with osteoporosis and early predictors of cardiovascular disease. The aim of this study was to evaluate whether these polymorphisms contribute to cardiovascular disease (CVD) in type 2 diabetic patients. We performed a case-control study with 178 CVD subjects with diabetes and 312 diabetic patients without CVD to assess the impact of variants of the OPG gene on the risk of CVD. The OPG gene polymorphisms were analyzed by using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). There was no significant association between the T245G and G1181C polymorphisms and CVD in the additive genetic model (OR = 0.96, 95% CI 0.64–1.45, p = 0.79; OR = 1.06, 95% CI 0.81–1.39, p = 0.65, respectively). However, the C allele of the T950C polymorphism was independently associated with a risk of CVD in type 2 diabetic patients in this genetic model (OR = 1.38, 95% CI 1.07–1.80, p = 0.01). This study provides evidence that the C allele of the T950C polymorphism is associated with increased risk of CVD in diabetic patients. However, well-designed prospective studies with a larger sample size are needed to validate these results.     

Association of kidney structure-related gene variants with type 2 diabetes-attributed end-stage kidney disease in African Americans

African Americans (AAs) are at higher risk for developing end-stage kidney disease (ESKD) compared to European Americans. Genome-wide association studies have identified variants associated with diabetic and non-diabetic kidney diseases. Nephropathy loci, including SLC7A9, UMOD, and SHROOM3, have been implicated in the maintenance of normal glomerular and renal tubular structure and function. Herein, 47 genes important in podocyte, glomerular basement membrane, mesangial cell, mesangial matrix, renal tubular cell, and renal interstitium structure were examined for association with type 2 diabetes (T2D)-attributed ESKD in AAs. Single-variant association analysis was performed in the discovery stage, including 2041 T2D-ESKD cases and 1140 controls (non-diabetic, non-nephropathy). Discrimination analyses in 667 T2D cases-lacking nephropathy excluded T2D-associated SNPs. Nominal associations were tested in an additional 483 T2D-ESKD cases and 554 controls in the replication stage. Meta-analysis of 4218 discovery and replication samples revealed three significant associations with T2D-ESKD at CD2AP and MMP2 (P _corr < 0.05 corrected for effective number of SNPs in each locus). Removal of APOL1 renal-risk genotype carriers revealed additional association at five loci, TTC21B, COL4A3, NPHP3-ACAD11, CLDN8, and ARHGAP24 (P _corr < 0.05). Genetic variants at COL4A3, CLDN8, and ARHGAP24 were potentially pathogenic. Gene-based associations revealed suggestive significant aggregate effects of coding variants at four genes. Our findings suggest that genetic variation in kidney structure-related genes may contribute to T2D-attributed ESKD in the AA population.     

Association of vitamin D receptor BsmI gene polymorphism with the risk of type 2 diabetes mellitus

Abstract

Relationship between vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism and the type 2 diabetes mellitus (T2DM) susceptibility is still conflicting at present. This meta-analysis was conducted to assess the association between VDR BsmI gene polymorphism and the risk of T2DM. The association studies were identified from PubMed, and Cochrane Library on 1 January 2014, and eligible investigations were included and synthesized using meta-analysis method. Eleven reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with T2DM susceptibility. In overall populations, B allele, BB genotype and bb genotype were not associated with T2DM risk. VDR BsmI gene polymorphism was also not associated with the T2DM risk in Asians and Caucasians. In conclusion, VDR BsmI gene polymorphism was also not associated with T2DM risk in overall populations, Asians and Caucasians. However, more studies should be conducted to confirm it.     

Genetic variants of diabetes risk and incident cardiovascular events in chronic coronary artery disease

Objective

To determine whether information from genetic risk variants for diabetes is associated with cardiovascular events incidence.

Methods

From the about 30 known genes associated with diabetes, we genotyped single-nucleotide polymorphisms at the 10 loci most associated with type-2 diabetes in 425 subjects from the MASS-II Study, a randomized study in patients with multi-vessel coronary artery disease. The combined genetic information was evaluated by number of risk alleles for diabetes. Performance of genetic models relative to major cardiovascular events incidence was analyzed through Kaplan-Meier curve comparison and Cox Hazard Models and the discriminatory ability of models was assessed for cardiovascular events by calculating the area under the ROC curve.

Results

Genetic information was able to predict 5-year incidence of major cardiovascular events and overall-mortality in non-diabetic individuals, even after adjustment for potential confounders including fasting glycemia. Non-diabetic individuals with high genetic risk had a similar incidence of events then diabetic individuals (cumulative hazard of 33.0 versus 35.1% of diabetic subjects). The addition of combined genetic information to clinical predictors significantly improved the AUC for cardiovascular events incidence (AUC = 0.641 versus 0.610).

Conclusions

Combined information of genetic variants for diabetes risk is associated to major cardiovascular events incidence, including overall mortality, in non-diabetic individuals with coronary artery disease.

Clinical Trial Registration Information

Medicine, Angioplasty, or Surgery Study (MASS II). Unique identifier: ISRCTN66068876 URL.     

Association between variants of EXT2 and type 2 diabetes: a replication and meta-analysis

Recent publications have found an association between variants of exostosin 2 (EXT2) gene and the risk of type 2 diabetes in some population but not in others. In an attempt to address these inconsistencies, we investigated EXT2 variants in two independent cohorts, and conducted a literature-based meta-analysis. Through regression model, we assessed the relationship between the EXT2 single nucleotide polymorphisms (SNPs) (rs3740878, rs11037909 and rs1113132) and the risk of type 2 diabetes in Han Chinese population, including a total of 2,533 cases and 2,643 controls. We combined our data with that from previously published studies and performed a meta-analysis to evaluate the effect size of the gene. Consistent with some studies, we found marginal association for the rs3740878 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.09), rs11037909 (OR = 1.07, 95 % CI = 0.99, 1.16, p = 0.08), and rs1113132 (OR = 1.08, 95 % CI = 1.00, 1.17, p = 0.06) in our 2 cohorts. Meta-analysis, comprising 9,224 type 2 diabetes and 10,484 controls, revealed that three SNPs (rs3740878, rs11037909 and rs1113132) in EXT2 were significantly associated with type 2 diabetes (ORs range from 1.06 to 1.07, p = 0.038, p = 0.008 and p = 0.005, respectively). Variation in the EXT2 locus appears to be associated with a small increase in the risk of type 2 diabetes. However, well-designed prospective studies with larger sample size and more ethnic groups are needed to further validate the results.     

Association of SGK1 gene polymorphisms with type 2 diabetes

The serum and glucocorticoid inducible kinase SGK1 is genomically upregulated by glucocorticoids and in turn stimulates a variety of carriers and channels including the renal epithelial Na(+) channel ENaC and the intestinal Na(+) glucose transporter SGLT1. Twin studies disclosed an association of a specific SGK1 haplotype with moderately enhanced blood pressure in individuals who are carrying simultaneously a homozygous genotype for a variant in intron 6 [I6CC] and a homozygous or heterozygous genotype for the C allele of a polymorphism in exon 8 [E8CC/CT] of the SGK1 gene. A subsequent study confirmed the impact of this risk haplotype on blood pressure. SGK1 knockout mice are resistant to the insulin and high salt induced increase of blood pressure, glucocorticoid induced increase of electrogenic glucose transport, and glucocorticoid induced suppression of insulin release. The present study explored whether the I6CC/E8CC/CT haplotype impacts on the prevalence of type 2 diabetes. The prevalence of the I6CC genotype was 3.1% in a healthy German, 2.4 % in a healthy Romanian and 11.6 % in a healthy African population from Ghana (p=0.0006 versus prevalence in Caucasians). Comparison of genotype frequencies between type 2 diabetic patients and the respective control groups revealed significant differences for the intron 6 T>C variant. Carriers of at least one T allele were protected against type 2 diabetes (Romanians: p=0.023; OR 0.29; 95% CI 0.09-0.89; Germans: p=0.01; OR 0.37; 95% CI 0.17-0.81). The SGK1 risk haplotype (I6CC/E8CC/CT) was significantly (p=0.032; OR 4.31, 95% CI 1.19-15.58) more frequent in diabetic patients (7.2 %) than in healthy volunteers from Romania (1.8%). The observations support the view that SGK-1 may participate in the pathogenesis of metabolic syndrome.     

Cardiovascular disease in diabetes mellitus type 2: a potential role for novel cardiovascular risk factors

A major consequence of diabetes mellitus type 2 is the accelerated development of atherosclerosis. Assessment of conventional risk factors such as plasma lipids, lipoproteins and hypertension only partly account for the excessive risk of developing cardiovascular disease in this population. Increasing evidence has emerged suggesting that conditions associated with diabetes mellitus type 2, such as insulin resistance, hyperinsulinemia and hyperglycemia, may also play a significant role in regulating 'novel' cardiovascular risk factors. These factors and their potential roles in the development of atherosclerosis and cardiovascular events are discussed in this review.     

Effects of 16 genetic variants on fasting glucose and type 2 diabetes in South Asians: ADCY5 and GLIS3 variants may predispose to type 2 diabetes

BackgroundThe Meta-Analysis of Glucose and Insulin related traits Consortium (MAGIC) recently identified 16 loci robustly associated with fasting glucose, some of which were also associated with type 2 diabetes. The purpose of our study was to explore the role of these variants in South Asian populations of Punjabi ancestry, originating predominantly from the District of Mirpur, Pakistan.Conclusions/SignificanceAlthough only the SLC30A8 rs11558471 SNP was nominally associated with fasting glucose in our study, the finding that 12 out of 16 SNPs displayed a direction of effect consistent with European studies suggests that a number of these variants may contribute to fasting glucose variation in individuals of South Asian ancestry. We also provide evidence for the first time in South Asians that alleles of SNPs in GLIS3 and ADCY5 may confer risk of type 2 diabetes.