Association Of Type 2 Diabetes Research Articles

Type 2 diabetes as a predictor of survival among breast cancer patients: the multiethnic cohort.

The purpose of the study was to investigate the association of type 2 diabetes (T2D) with survival of breast cancer (BC) patients across five ethnic groups within the Multiethnic Cohort study. Between recruitment in 1993-1996 and 2013, 7570 incident BC cases were identified through SEER cancer registries in Hawaii and California. T2D diagnosed before BC was ascertained in 1013 women from self-reports and confirmed by administrative data sources. Covariate information was collected by questionnaire. Cox regression analysis with age as the time metric and BMI as time-varying exposure was applied to estimate hazard ratios (HR) and 95% confidence intervals (CI) for BC-specific and all-cause survival while adjusting for known prognostic factors. In total, 2119 all-cause and 730 BC-specific deaths were recorded with corresponding 5-year survival rates of 86 and 93%. T2D was not a significant predictor of BC-specific survival (HR 0.84; 95% CI 0.65-1.09), but mortality was 36% lower for those with < 7years of T2D than a longer history of T2D. On the other hand, all-cause mortality was higher in women with T2D (HR 1.23; 95% CI 1.08-1.40), especially in women with T2D of ≥ 7years duration (HR 1.27; 95% CI 1.07-1.49). In women receiving none or either chemotherapy or radiation but not both, T2D predicted higher all-cause mortality (Pinteraction = 0.004). Variations in the association of T2D with mortality across ethnic groups were small. T2D was associated with higher all-cause but notBC-specific mortality among women with BCin the Multiethnic Cohort study. However, T2D affected survival in cases who did not receive both radiation and chemotherapy.

The Mediterranean diet and risk of type 2 diabetes in Iranian population.

Type 2 diabetes (T2D) is fast increasing in recent decades. Limited prospective studies are available on Mediterranean diet protective effect against T2D development. We assessed longitudinal association of the Mediterranean diet with T2D risk in Iranian men and women. Diet was measured using a 168-item food frequency questionnaire in 2139 adults (free of T2D), aged 20-70 years. All individuals, based on the traditional Mediterranean diet score (MDS), received scores between 0 and 8 points. Multivariate hazard ratio (HR) and 95% confidence interval (CI) were reported for the association of T2D and the MDS, with adjustment of diabetes risk score (DRS) and dietary energy intakes. During follow-up, a total of 143 events occurred. Individuals who had higher intakes of fish/sea foods, legumes, nuts, and monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) ratio had a decreased risk of T2D. After adjustment for confounders, an inverse association was found between adherence to the MDS and T2D (HR = 0.48; 95% CI 0.27-0.83). Our findings demonstrated an inverse association between the Mediterranean diet score and incidence of T2D.

Association between genetic risk variants and glucose intolerance during pregnancy in north Indian women

BackgroundGestational diabetes (GDM) is a more common problem in India than in many other parts of the world but it is not known whether this is due to unique environmental factors or a unique genetic background. To address this question we examined whether the same genetic variants associated with GDM and Type 2 Diabetes (T2D) in Caucasians also were associated with GDM in North Indian women.MethodsFive thousand one hundred pregnant women of gestational age 24–28 weeks from Punjab were studied by a 75 g oral glucose tolerance test (OGTT). GDM was diagnosed by both WHO1999 and 2013 criteria. 79 single nucleotide polymorphisms (SNPs) previously associated with T2D and glycemic traits (12 of them also with GDM) and 6 SNPs from previous T2D associations based on Indian population (some also with European) were genotyped on a Sequenom platform or using Taqman assays in DNA from 4018 women.ResultsIn support of previous findings in Caucasian GDM, SNPs at KCJN11 and GRB14 loci were nominally associated with GDM1999 risk in Indian women (both p = 0.02). Notably, T2D risk alleles of the variant rs1552224 near CENTD2, rs11708067 in ADCY5 and rs11605924 in CRY2 genes associated with protection from GDM regardless of criteria applied (p < 0.025). SNPs rs7607980 near COBLL1 (p = 0.0001), rs13389219 near GRB14 (p = 0.026) and rs10423928 in the GIPR gene (p = 0.012) as well as the genetic risk score (GRS) for these previously shown insulin resistance loci here associated with insulin resistance defined by HOMA2-IR and showed a trend towards GDM. GRS comprised of 3 insulin secretion loci here associated with insulin secretion but not GDM.ConclusionsGDM in women from Punjab in Northern India shows a genetic component, seemingly driven by insulin resistance and secretion and partly shared with GDM in other parts of the world. Most previous T2D loci discovered in European studies did not associate with GDM in North India, indicative of different genetic etiology or alternately, differences in the linkage disequilibrium (LD) structure between populations in which the associated SNPs were identified and Northern Indian women. Interestingly some T2D risk variants were in fact indicative of being protective for GDM in these Indian women.

Abstract 235: Type 2 diabetes and glycemic traits in relation to colorectal cancer risk: A Mendelian randomization study

Abstract Background: Although type 2 diabetes (T2D) has been linked to an increased risk of colorectal cancer (CRC), a causal relationship remains to be established. Also, the influence of hyperglycemia and impaired beta-cell function on CRC remains to be determined. Methods: We performed a Mendelian randomization (MR) study using common single nucleotide polymorphisms (SNPs) identified from prior genome-wide association studies for T2D (78 SNPs), fasting glucose (36 SNPs), glycosylated hemoglobin (HbA1c, 11 SNPs), and homeostatic model assessment for beta-cell function (HOMA-B, 13 SNPs) (all SNPs reached genome-wide significance at 5 x10-8). We first assessed the association of each SNP with CRC risk using logistic regression in 26,357 CRC cases and 20,505 control participants in the Colon Cancer Family Registry, Colorectal Transdisciplinary Study and the Genetics and Epidemiology of Colorectal Cancer Consortium. The MR estimates for the association of each risk factor with CRC were calculated using the inverse-variance weighted method that combines summary data on the association of the SNPs with each trait derived from previous genome-wide association studies. Given the potential sex difference in the relationship of metabolic factors with CRC, all analyses were performed in men and women separately. Results: We did not find any statistically significant association between each of the genetically predicted risk factors and CRC incidence for sex-stratified or combined analyses. The odds ratios (ORs) of CRC associated with genetic risk of T2D were 1.02 (95% confidence interval [CI], 0.95-1.08, P=0.62) in women and 0.96 (95% CI, 0.90-1.03, P=0.25) in men. For fasting glucose, the ORs of CRC associated with one mmol/L increment was 0.91 (95% CI, 0.68-1.20, P=0.49) in women and 1.20 (95% CI, 0.90-1.59, P=0.22) in men, respectively. For HbA1c, the ORs of CRC associated with one percent increment was 0.83 (95% CI, 0.57-1.22, P=0.35) in women and 0.99 (95% CI, 0.67-1.45, P=0.95) in men. For HOMA-B, the ORs of CRC associated with a unit increase in log-transformed measurement was 0.92 (95% CI, 0.53-1.60, P=0.76) in women and 0.77 (95% CI, 0.44-1.35, P=0.36) in men. Conclusion: Our findings do not support a causal association of T2D, impaired beta-cell function, and hyperglycemia with CRC risk. However, the null findings may be due to weak instrument bias since these common SNPs account for only a limited proportion of the inter-individual variation in these glycemic traits. Citation Format: Mingyang Song, Yiwen Lu, Marc Gunter, Neil Murphy, Barbara L. Banbury, Wenjie Ma, Jennifer Prescott, Graham Casey, Stephen B. Gruber, Edward L. Giovannucci, Ulrike Peters, Andrew T. Chan. Type 2 diabetes and glycemic traits in relation to colorectal cancer risk: A Mendelian randomization study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 235.

Discovery and Fine-Mapping of Type 2 Diabetes Susceptibility Loci in Diverse Populations Using More than a Million Individuals

To discover type 2 diabetes (T2D) loci and enhance fine-mapping resolution, we conducted the largest meta-analysis of genome-wide association studies of the disease to date by aggregating 171,262 cases and 1,075,072 controls from diverse populations (45% non-European ancestry). We identified 250 loci at genome-wide significance (p&amp;lt;5x10-8); 59 mapped outside regions previously implicated in T2D. Across these loci, conditional analyses revealed a total of 475 distinct signals of association (locus-wide significance, p&amp;lt;10-5). We observed strong evidence of heterogeneity in allelic effects on T2D (pHET&amp;lt;1.4x10-4, Bonferroni correction) correlated with ancestry at 17% of signals, including LEP (rs35589574, pHET=4.8x10-25, East Asian specific) and multiple associations at/near KCNQ1 and TCF7L2 (representing ethnic-specific/-differentiated effects). T2D-associated variants showed significant enrichment (odds-ratio range 1.90-6.63; p&amp;lt;0.05) in coding exons, pancreatic islet enhancers and promoters, adipose enhancers, and binding sites for transcription factors, including NKX2.2 and FOXA2. Increased sample size, population diversity, and annotation-informed fine-mapping substantially improved localisation of potential causal variants compared with previous efforts, and highlighted 76 signals with a single variant accounting for &amp;gt;80% of the posterior probability of association (PPA); of these 35 signals had PPA of &amp;gt;99%. Clustering of signal-specific annotation enrichment highlighted distinct clades of T2D associations driven by different underlying molecular processes. These analyses represent the most comprehensive view of the genetic contribution to T2D to date and, through integration with expression quantitative trait loci in disease-relevant tissues, point to previously unreported effector genes (such as SKOR1, CLUAP1, and PEPD) and mediating molecular mechanisms at several loci. Disclosure H. Kitajima: None. X. Sim: None. M. Ng: None. W. Zhang: None. J.E. Below: None. A.J. Payne: None. K. Gaulton: None. A. Morris: None.

Dietary patterns and type 2 diabetes among Ghanaian migrants in Europe and their compatriots in Ghana: the RODAM study

Background/objectivesWe aimed to study the associations of dietary patterns (DPs) with type 2 diabetes (T2D) among Ghanaian adults.Subjects/methodsIn the multi-centre, cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study (n = 4543), three overall DPs (“mixed”, “rice, pasta, meat and fish,” and “roots, tubers and plantain”) and two site-specific DPs per study site (rural Ghana, urban Ghana and Europe) were identified by principal component analysis. The DPs–T2D associations were calculated by logistic regression models.ResultsHigher adherence to the “rice, pasta, meat and fish” DP (characterized by legumes, rice/pasta, meat, fish, cakes/sweets, condiments) was associated with decreased odds of T2D, adjusted for socio-demographic factors, total energy intake and adiposity measures (odds ratio (OR)per 1 SD = 0.80; 95% confidence interval (CI) = 0.70–0.92). Similar DPs and T2D associations were discernible in urban Ghana and Europe. In the total study population, neither the “mixed” DP (whole grain cereals, sweet spreads, dairy products, potatoes, vegetables, poultry, coffee/tea, sodas/juices, olive oil) nor the “roots, tubers and plantain” DP (refined cereals, fruits, nuts/seeds, roots/tubers/plantain, fermented maize products, legumes, palm oil, condiments) was associated with T2D. Yet, after the exclusion of individuals with self-reported T2D, the “roots, tubers and plantain” DP was inversely associated with T2D (ORper 1 SD = 0.88; 95% CI = 0.69–1.12).ConclusionIn this Ghanaian population, DPs characterized by the intake of legumes, fish, meat and confectionery were inversely associated with T2D. The effect of a traditional-oriented diet (typical staples, vegetables and legumes) remains unclear.

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.

Individual risk of type 2 diabetes (T2D) is modified by perturbations of adipose mass, distribution and function. To investigate mechanisms responsible, we explored the molecular, cellular, and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression, and modulate, in trans, expression of 385 genes. We demonstrate that, in human cellular studies, reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and, in mice, adipose-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that KLF14 T2D risk-allele carriers shift body fat from gynoid to abdominal stores, and display a marked increase in adipocyte cell size: these effects on fat distribution, and the T2D-association, are female-specific. Metabolic risk associated with variation at this imprinted locus depends on both the sex of the subject, and of the parent from whom the risk-allele derives.

Review: Relationship of type 2 diabetes to human brain pathology.

Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both highly prevalent diseases worldwide, and each is associated with high-morbidity and high-mortality. Numerous clinical studies have consistently shown that T2D confers a two-fold increased risk for a dementia, including dementia attributable to AD. Yet, the mechanisms underlying this relationship, especially nonvascular mechanisms, remain debated. Cerebral vascular disease (CVD) is likely to be playing a role. But increased AD neuropathologic changes (ADNC), specifically neuritic amyloid plaques (AP) and neurofibrillary tangles (NFT), are also posited mechanisms. The clinicopathological studies to date demonstrate T2D to be consistently associated with infarcts, particularly subcortical lacunar infarcts, but not ADNC, suggesting the association of T2D with dementia may largely be mediated through CVD. Furthermore, growing interest exists in insulin resistance (IR), particularly IR within the brain itself, which may be an associated but distinct phenomenon from T2D, and possibly itself associated with ADNC. Other mechanisms largely related to protein processing and efflux in the central nervous system with altered function in T2D may also be involved. Such mechanisms include islet amyloid polypeptide (or amylin) deposition, co-localized with beta-amyloid and found in more abundance in the AD temporal cortex, blood-brain barrier breakdown and dysfunction, potentially related to pericyte degeneration, and disturbance of brain lymphatics, both in the glial lymphatic system and the newly discovered discrete central nervous system lymph vessels. Medical research is ongoing to further disentangle the relationship of T2D to dementia in the ageing human brain.

Neighborhood characteristics, food deserts, rurality, and type 2 diabetes in youth: Findings from a case-control study

Little is known about the influence of neighborhood characteristics on risk of type 2 diabetes (T2D) among youth. We used data from the SEARCH for Diabetes in Youth Case-Control Study to evaluate the association of neighborhood characteristics, including food desert status of the census tract, with T2D in youth. We found a larger proportion of T2D cases in tracts with lower population density, larger minority population, and lower levels of education, household income, housing value, and proportion of the population in a managerial position. However, most associations of T2D with neighborhood socioeconomic characteristics were attributable to differences in individual characteristics. Notably, in multivariate logistic regression models, T2D was associated with living in the least densely populated study areas, and this finding requires further exploration.

RNASEH1 gene variants are associated with autoimmune type 1 diabetes in Colombia.

In a previous work, we found linkage and association of type 1 diabetes (T1D) to a 12 known gene region at chromosome 2p25 in Colombian families. Here, we present further work on this candidate region. Seventeen SNPs located on the 12 candidate genes, in 100 familial trios set, were tested by ARMS-tetraprimer-PCR or PCR-RFLP. Five extra SNPs in the vicinity of rs10186193 were typed. A replica phase included 97 novel familial trios, in whom diabetes-related auto-antibodies (AABs) were tested in sera of the patients. In addition to transmission disequilibrium tests, haplotype analyses were carried out using the unphased software. SNP rs10186193 (at RNASEH1 gene) showed association with T1D (P=0.005). The additional five SNPs revealed that rs7607888 (P=2.03×10-7), rs55981318 (P=0.018), and rs1136545 (P=1.93×10-9) were also associated with T1D. Haplotype analysis showed association for rs55981318-rs10186193 (P=0.0005), rs7563960-rs7607888 (P=0.0007), rs7607888-rs1136545 (P=9.21×10-10), and rs1136545-rs11538545 (P=6.67×10-8). In contrast, the new set of 97 familial trios tested for SNPs rs55981318, rs10186193, and rs7607888 did not support the previous finding; however, by combining the sample (197 trios), evidence of association of T1D with rs55981318 and rs7607888 was conclusive. In addition, a two-loci haplotype analysis of the combined sample showed significant association of RNASEH1 with T1D (P=3.1×10-5). In conclusion, our analyses suggest that RNASEH1 gene variants associate with susceptibility/protection to T1D in Colombia.

Direct Analysis of Insulin-Specific T Cells Provides New Insights.

Type 1 diabetes (T1D) is an autoimmune disease in which destruction of insulin-producing β-cells leads to dependence on exogenous insulin (1). T1D progression involves progressive loss of tolerance to β-cell antigens, but this has been challenging to observe in human disease. Loss of self-tolerance is most evident through development of islet cell antibodies, among which insulin antibodies typically appear first (2). Given strong genetic association of T1D with HLA-DQ8, DQ8-restricted CD4+ T cells activated by self-peptides are thought to play a crucial role in disease. Key evidence from the nonobese diabetic (NOD) mouse model supports a primary role for recognition of an epitope within the insulin B chain amino acids 9–23 (InsB9–23) peptide in disease initiation. The majority of CD4+ T cells isolated from pancreatic islets of NOD mice were shown to respond to this peptide (3). Furthermore, expression of an insulin transgene with a substitution within this peptide abrogated diabetes development (4). Efforts to directly visualize and study insulin-specific T cells in human subjects have been hampered by the biochemical instability of the HLA-DQ8 protein (5). However, recent reports highlight the development of HLA-DQ8 tetramer reagents and their application to study T1D, affirming that InsB11–23 peptide is analogously presented by IAg7 and HLA-DQ8 (6,7). In addition, two recent reports documented the presence …

Alzheimer's desease and insulin resistance

Background: The number of patients with dementia is growing rapidly as the population ages. Dietary factors are important from the view point of public health since they are potentially modifiable and maintaining optimal nutritional status has been expected to be a desirable approach for prevention of dementia. Another nutritional topic on dementia and diet is the association of type-2 diabetes (T2D) and hyerinsulinemia with Alzheimer's disease (AD). Neuropathological survey in the Hisayama study, has shown that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate the formation of neuritic plaques suggesting that T2D is a major risk factor for AD.

Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin.

Inverse relationships have been described between the largely genetically determined levels of serum/plasma lipoprotein(a) [Lp(a)], type 2 diabetes (T2D) and fasting insulin. Here, we aimed to evaluate the nature of these relationships with respect to causality. We tested whether we could replicate the recent negative findings on causality between Lp(a) and T2D by employing the Mendelian randomization (MR) approach using cross-sectional data from three independent cohorts, Berlin Aging Study II (BASE-II; n = 2012), LIFE-Adult (n = 3281) and LIFE-Heart (n = 2816). Next, we explored another frequently discussed hypothesis in this context: Increasing insulin levels during the course of T2D disease development inhibits hepatic Lp(a) synthesis and thereby might explain the inverse Lp(a)-T2D association. We used two fasting insulin-associated variants, rs780094 and rs10195252, as instrumental variables in MR analysis of n = 4937 individuals from BASE-II and LIFE-Adult. We further investigated causality of the association between fasting insulin and Lp(a) by combined MR analysis of 12 additional SNPs in LIFE-Adult. While an Lp(a)-T2D association was observed in the combined analysis (meta-effect of OR [95% CI] = 0.91 [0.87-0.96] per quintile, p = 1.3x10-4), we found no evidence of causality in the Lp(a)-T2D association (p = 0.29, fixed effect model) when using the variant rs10455872 as the instrumental variable in the MR analyses. Likewise, no evidence of a causal effect of insulin on Lp(a) levels was found. While these results await confirmation in larger cohorts, the nature of the inverse Lp(a)-T2D association remains to be elucidated.

Insulin resistance is associated with reductions in specific cognitive domains and increases in CSF tau in cognitively normal adults

Growing evidence supports the hypothesis that type 2 diabetes (T2D) increases the risk of developing dementia. Experimental evidence from mouse models demonstrates that the induction of T2D/insulin resistance (IR) can promote the accumulation of Alzheimer’s disease (AD) pathological features. However, the association of T2D with pathological and clinical phenotypes in humans is unclear. Here we investigate the relationship of indices of IR (HOMA-IR) and pancreatic β-cell function (HOMA-B) with cognitive performance across several domains (Verbal/Visual Episodic Memory, Executive Function, Language and a measure of Global cognition) and AD biomarkers (CSF Aβ42, T-tau/P-tau, hippocampal volume and neocortical Aβ-amyloid burden). We reveal that HOMA-IR (p < 0.001) incrementally increases across diagnostic groups, becoming significantly elevated in the AD group compared with cognitively normal (CN) adults. In CN adults, higher HOMA-IR was associated with poorer performance on measures of verbal episodic memory (p = 0.010), executive function (p = 0.046) and global cognition (p = 0.007), as well as with higher CSF T-tau (p = 0.008) and P-tau (p = 0.014) levels. No association was observed with CSF Aβ or imaging modalities. Together our data suggest that IR may contribute to reduced cognitive performance and the accumulation of CSF tau biomarkers in cognitively normal adults.

The association of type II diabetes with gut microbiota composition

It is known that type 2 diabetes (T2D) in humans could be linked to the composition of gut microbiota. The aim of this study was to evaluate three faecal bacterial species, including Bacteroides fragilis, Bifidobacterium longum and Faecalibacterium prausnitzii in patients with T2D. This case control study included 18 patients with T2D and 18 matched persons without diabetes. The concentrations of B. fragilis, B. longum and F. prausnitzii were determined by quantitative Real-Time PCR. Quantitative PCR analysis revealed that the gut bacterial composition in patients with T2D was partially different from that in the healthy individuals. Faecalibacterium prausnitzii was significantly lower in patients with T2D (P-value = 0.038). Bacteroides fragilis was under-represented in the microbiota of the group with diabetes, but its difference between two groups was not significant (P-value = 0.38). No difference was observed for B. longum community between the both groups (P-value = 0.99). Characterization of specific species of intestinal microbiota shows some compositional changes in patients with T2D. The results may be valuable for developing strategies to control type 2 diabetes by modifying the intestinal microbiota. Long-term studies with emphasis on other bacterial groups are suggested to clarify the association of T2D with gut microbiota.

Meta-analyses of the association of G6PC2 allele variants with elevated fasting glucose and type 2 diabetes.

ObjectiveTo collectively evaluate the association of glucose-6-phosphatase catalytic unit 2 (G6PC2) allele variants with elevated fasting glucose (FG) and type 2 diabetes (T2D).DesignMeta-analysisData sourcesPubMed, Web of Knowledge and Embase databases.Study selectionFull text articles of studies that identified an association of G6PC2 with T2D and elevated FG.Patient involvementThere was no T2D patient involvement in the analyses on the association of FG with G6PC2, there were T2D patients and non-diabetes patient involvement in the analyses on the association of T2D with G6PC2.Statistical analysisRandom-effects meta-analyses were used to calculate the pool effect sizes. I2 metric and H2 tests were used to calculate the heterogeneity. Begg's funnel plot and Egger’s linear regression test were done to assess publication bias.ResultsOf the 423 studies identified, 21 were eligible and included. Data on three loci (rs560887, rs16856187 and rs573225) were available. The G allele at rs560887 in three ethnicities, the C allele at rs16856187 and the A allele at rs573225 all had a positive association with elevated FG. Per increment of G allele at rs560887 and A allele at rs573225 resulted in a FG 0.070 mmol/l and 0.075 mmol/l higher (ß (95% CI) = 0.070 (0.060, 0.079), p = 4.635e-50 and 0.075 (0.065, 0.085), p = 5.856e-48, respectively). With regard to the relationship of rs16856187 and FG, an increase of 0.152 (95% CI: 0.034–0.270; p = 0.011) and 0.317 (95% CI: 0.193–0.442, p = 6.046e-07) was found in the standardized mean difference (SMD) of FG for the AC and CC genotypes, respectively, when compared with the AA reference genotype. However, the G-allele of rs560887 in Caucasians under the additive model and the C-allele of rs16856187 under the allele and dominant models were associated with a decreased risk of T2D (OR (95% CI) = 0.964 (0.947, 0.981), p = 0.570e-4; OR (95% CI) = 0.892 (0.832, 0.956), p = 0.001; and OR (95% CI) = 0.923(0.892, 0.955), p = 5.301e-6, respectively).ConclusionsOur meta-analyses demonstrate that all three allele variants of G6PC2 (rs560887, rs16856187 and rs573225) are associated with elevated FG, with two variants (rs560887 in the Caucasians subgroup and rs16856187 under the allele and dominant model) being associated with T2D as well. Further studies utilizing larger sample sizes and different ethnic populations are needed to extend and confirm these findings.

A comparison of gene expression profiles in patients with coronary artery disease, type 2 diabetes, and their coexisting conditions

BackgroundTo support a hypothesis that there is an intrinsic interplay between coronary artery disease (CAD) and type 2 diabetes (T2D), we used RNA-seq to identify unique gene expression signatures of CAD, T2D, and coexisting conditions.MethodsAfter transcriptome sequencing, differential expression analysis was performed between each disordered state and normal control group. By comparing gene expression profiles of CAD, T2D, and coexisting conditions, common and specific patterns of each disordered state were displayed. To verify the specific gene expression patterns of CAD or T2D, the gene expression data of GSE23561 was extracted.ResultsA strong overlap of 191 genes across CAD, T2D and coexisting conditions, were mainly involved in a viral infectious cycle, anti-apoptosis, endocrine pancreas development, innate immune response, and blood coagulation. In T2D-specific PPI networks involving 64 genes, TCF7L2 (Degree = 169) was identified as a key gene in T2D development, while in CAD-specific PPI networks involving 64 genes, HIF1A (Degree = 124), SMAD1 (Degree = 112) and SKIL (Degree = 94) were identified as key genes in the CAD development. Interestingly, with the provided expression data from GSE23561, the three genes were all up-regulated in CAD, and SMAD1 and SKIL were specifically differentially expressed in CAD, while HIF1A was differentially expressed in both CAD and T2D, but with opposite trends.ConclusionsThis study provides some evidences in transcript level to uncover the association of T2D, CAD and coexisting conditions, and may provide novel drug targets and biomarkers for these diseases.

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.

The systolic-diastolic difference in carotid stiffness is increased in type 2 diabetes: The Maastricht Study.

In type 2 diabetes (T2D), increased arterial stiffening results from accelerated arterial wall matrix remodeling. The associated structural alterations modify the pressure dependency of arterial stiffness, which can be quantified by the systolic-diastolic difference in carotid pulse wave velocity (δPWV). We evaluated the association between T2D and δPWV as marker for matrix remodeling and whether δPWV may contain additional information beyond carotid stiffness (cPWV). In 746 individuals from The Maastricht Study, 415 with normal glucose metabolism; 126 with prediabetes; and 205 with T2D, carotid pulse wave velocity (cPWV) and δPWV were determined by ultrasonography and tonometry. Multiple linear regression analyses were used to investigate associations of glucose metabolism status (with normal glucose metabolism as reference) with cPWV and δPWV, adjusting for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, and δPWV or cPWV as appropriate. After adjustment for age, sex, mean arterial pressure, prior cardiovascular disease, estimated glomerular filtration rate and smoking, T2D was associated with greater cPWV [β (95% confidence interval) 0.376 (0.119; 0.632)] and δPWV [0.301 (0.013; 0.589)]. After additional adjustment for δPWV or cPWV, associations of T2D with cPWV and δPWV were attenuated [0.294 (0.048; 0.539) and 0.173 (-0.103; 0.449), respectively]. Prediabetes was not associated with either cPWV or δPWV. The systolic-diastolic difference in carotid stiffness is increased in T2D, but not prediabetes. Importantly, the association was not abolished by carotid stiffness, which suggests that systolic-diastolic difference in carotid stiffness carries additional information regarding arterial matrix remodeling.

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

BackgroundIn adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as ‘latent autoimmune diabetes in adults’ (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes.MethodsWe tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls.ResultsOverall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted.ConclusionLADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.