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The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = 20.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = 20.21, P = 5 3 10-6) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology. [ABSTRACT FROM AUTHOR]

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity. [ABSTRACT FROM AUTHOR]

Rh(III)-catalyzed ortho C-H olefination of aryl sulfonamide directed by the SO2NHAc group is reported. This oxidative coupling process is achieved highly efficiently and selectively with a broad substrate scope. The reactions of N-tosylacetamide with acrylate esters afford ortho-alkenylated benzofused five-membered cyclic sulfonamides, whereas styrenes provide the direct diolefination products. [ABSTRACT FROM AUTHOR]

Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity--related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites--glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)--and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits. [ABSTRACT FROM AUTHOR]

An efficient ruthenium-catalyzed oxidative coupling of indoles and pyrroles with various alkenes at the C2-position assisted by employing the N,N-dimethylcarbamoyl moiety as a directing group is reported. The catalytic reaction proceeds in an excellent regio- and stereoselective manner. [ABSTRACT FROM AUTHOR]

A facile and highly diastereoselective approach toward the synthesis of potent salacinol-type α-glucosidase inhibitors, originally isolated from plants of the genus "Salacia", was developed using the S-alkylation of thiosugars with epoxides in HFIP (~90%, dr, α/β = ~ 26/1). The dr ratio of the product was significantly improved by the protocol as compared to that of the conventional S-alkylation of thiosugars (dr, α/β = ~ 8/1). The protocol could be used for gram scale synthesis of the desired compounds. The 3'-O-benzylated salacinol analogs, which are the most potent in vitro inhibitors to date, were synthesized and evaluated in vivo; all analogs suppressed blood glucose levels in maltose-loaded mice, at levels comparable to those of the antidiabetic agent, voglibose. [ABSTRACT FROM AUTHOR]

Rhododendron delavayi Franch. is globally famous as an ornamental plant. Its distribution in southwest China covers several different habitats and environments. However, not much research had been conducted on Rhododendron spp. at the molecular level, which hinders understanding of its evolution, speciation, and synthesis of secondary metabolites, as well as its wide adaptability to different environments. Here, we report the genome assembly and gene annotation of R. delavayi var. delavayi (the second genome sequenced in the Ericaceae), which will facilitate the study of the family. The genome assembly will have further applications in genome-assisted cultivar breeding. The final size of the assembled R. delavayi var. delavayi genome (695.09 Mb) was close to the 697.94 Mb, estimated by k-mer analysis. A total of 336.83 gigabases (Gb) of raw Illumina HiSeq 2000 reads were generated from 9 libraries (with insert sizes ranging from 170 bp to 40 kb), achieving a raw sequencing depth of x482.6. After quality filtering, 246.06 Gb of clean reads were obtained, giving x352.55 coverage depth. Assembly using Platanus gave a total scaffold length of 695.09 Mb, with a contig N50 of 61.8 kb and a scaffold N50 of 637.83 kb. Gene prediction resulted in the annotation of 32 938 protein-coding genes. The genome completeness was evaluated by CEGMA and BUSCO and reached 95.97% and 92.8%, respectively. The gene annotation completeness was also evaluated by CEGMA and BUSCO and reached 97.01% and 87.4%, respectively. Genome annotation revealed that 51.77% of the R. delavayi genome is composed of transposable elements, and 37.48% of long terminal repeat elements (LTRs). The de novo assembled genome of R. delavayi var. delavayi (hereinafter referred to as R. delavayi) is the second genomic resource of the family Ericaceae and will provide a valuable resource for research on future comparative genomic studies in Rhododendron species. The availability of the R. delavayi genome sequence will hopefully provide a tool for scientists to tackle open questions regarding molecular mechanisms underlying environmental interactions in the genus Rhododendron, more accurately understand the evolutionary processes and systematics of the genus, facilitate the identification of genes encoding pharmaceutically important compounds, and accelerate molecular breeding to release elite varieties. [ABSTRACT FROM AUTHOR]

The cytotoxicity of the natural ent-kaurene diterpenoid, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing various substituents on 14-OH position, were designed, synthesized, and evaluated for anticancer efficacy. Some of the derivatives were significantly more potent than oridonin against both drug-sensitive and drug-resistant cancer cells. The most potent compound, 13p, was 200-fold more efficacious than oridonin in MCF-7 cancer cells. Furthermore, 13p induced apoptosis and cell cycle arrest at the G2/M phase. A decrease in mitochondrial membrane potential and an increase in Bax/Bcl-2 ratio, accompanied by activated caspase-3 cleavage, were observed in MCF-7 cells after treatment with 13p, suggesting that the mitochondrial pathway was involved in the 13p-mediated apoptosis. Moreover, 13p significantly inhibited tumor growth in mouse xenograft models and had no observable toxic effect. [ABSTRACT FROM AUTHOR]

A recent study identified a low-frequency variant at CCND2 associated with lower risk of type 2 diabetes, enhanced insulin response to a glucose challenge, higher height, and, paradoxically, higher BMI. We aimed to replicate the strength and effect size of these associations in independent samples and to assess the underlying mechanism. We genotyped the variant in 29,956 individuals and tested its association with type 2 diabetes and related traits. The low-frequency allele was associated with a lower risk of type 2 diabetes (OR 0.53; P =2 x 10-13; 6,647 case vs. 12,645 control subjects), higher disposition index (β = 0.07 log 10; P = 2 x 10-11; n = 13,028), and higher Matsuda index of insulin sensitivity (β = 0.02 log 10; P = 5 x 10-3; n = 13,118) but not fasting proinsulin (β = 0.01 log 10; P = 0.5; n = 6,985). The low frequency allele was associated with higher adult height (β =1.38 cm; P = 6 x 10-9; n = 13,927), but the association of the variant with BMI (β = 0.36 kg/m²; P = 0.02; n = 24,807), estimated in four population-based samples, was less than in the original publication where the effect estimate was biased by analyzing case subjects with type 2 diabetes and control subjects without diabetes separately. Our study establishes that a low-frequency allele in CCND2 halves the risk of type 2 diabetes primarily through enhanced insulin secretion. [ABSTRACT FROM AUTHOR]

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics--based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]