Type 2 diabetes (T2D) is a chronic metabolic disease defined by insulin insensitivity corresponding to impaired insulin sensitivity, decreased insulin production, and eventually failure of beta cells in the pancreas. There is a 30–40 percent higher risk of developing T2D in active smokers. Moreover, T2D patients with active smoking may gradually develop many complications. However, there is still no significant research conducted to solve the issue. Hence, we have proposed a highthroughput network-based quantitative pipeline employing statistical methods. Transcriptomic and GWAS data were analysed and obtained from type 2 diabetes patients and active smokers. Differentially Expressed Genes (DEGs) resulted by comparing T2D patients’ and smokers’ tissue samples to those of healthy controls of gene expression transcriptomic datasets. We have found 55 dysregulated genes shared in people with type 2 diabetes and those who smoked, 27 of which were upregulated and 28 of which were downregulated. These identified DEGs were functionally annotated to reveal the involvement of cell-associated molecular pathways and GO terms. Moreover, protein–protein interaction analysis was conducted to discover hub proteins in the pathways. We have also identified transcriptional and post-transcriptional regulators associated with T2D and smoking. Moreover, we have analysed GWAS data and found 57 common biomarker genes between T2D and smokers. Then, Transcriptomic and GWAS analyses are compared for more robust outcomes and identified 1 significant common gene, 19 shared significant pathways and 12 shared significant GOs. Finally, we have discovered protein–drug interactions for our identified biomarkers.

• GSEA
• Type-2 diabetes
• association
• bioinformatics
• orthology
• pathway
• smoking

• Biomarkers
• Computational Biology/methods
• Diabetes Mellitus, Type 2/metabolism
• Gene Expression Profiling
• Genome-Wide Association Study/methods
• Humans
• Insulin
• Smoking/adverse effects
• Smoking/genetics

• Development origins of health and diseases
• Environmental insults
• Epigenetics
• Human embryonic stem cells
• Maternal diabetes
• Type 2 diabetes

• DNA methylation
• Rho guanine nucleotide exchange Factor 11
• epigenetics
• gestational diabetes mellitus
• macrosomia
• obesity

• Animals
• Blood Glucose/metabolism
• Diabetes, Gestational/blood
• Diabetes, Gestational/genetics
• Diabetes, Gestational/metabolism
• Energy Metabolism
• Fatty Liver/genetics
• Fatty Liver/metabolism
• Female
• Glycolipids/blood
• Guanine Nucleotide Exchange Factors/genetics
• Guanine Nucleotide Exchange Factors/metabolism
• Insulin Resistance
• Liver/metabolism
• Liver/pathology
• Male
• Muscle, Skeletal/metabolism
• Obesity/blood
• Obesity/genetics
• Obesity/metabolism
• Phosphatidylinositol 3-Kinase/metabolism
• Phosphorylation
• Pregnancy
• Prenatal Exposure Delayed Effects
• Proto-Oncogene Proteins c-akt/metabolism
• Rats, Wistar
• Severity of Illness Index
• Signal Transduction
• rho-Associated Kinases/metabolism

Calcineurin inhibitors are used in immunosuppressive therapy applied after transplantation, but they are associated with major metabolic side effects including the development of new onset diabetes. Previously, we have shown that the calcineurin inhibiting drugs tacrolimus and cyclosporin A reduce adipocyte and myocyte glucose uptakes by reducing the amount of glucose transporter type 4 (GLUT4) at the cell surface, due to an increased internalization rate. However, this happens without alteration in total protein and phosphorylation levels of key proteins involved in insulin signalling or in the total amount of GLUT4. The present study evaluates possible pathways involved in the altered internalization of GLUT4 and consequent reduction of glucose uptake provoked by calcineurin inhibitors in human subcutaneous adipose tissue. Short- and long-term treatments with tacrolimus, cyclosporin A or another CNI deltamethrin (herbicide) decreased basal and insulin-dependent glucose uptake in adipocytes, without any additive effects observed when added together. However, no tacrolimus effects were observed on glucose uptake when gene transcription and protein translation were inhibited. Investigation of genes potentially involved in GLUT4 trafficking showed only a small effect on ARHGEF11 gene expression (p < 0.05). In conlusion, the specific inhibition of calcineurin, but not that of protein phosphatases, decreases glucose uptake in human subcutaneous adipocytes, suggesting that calcineurin is an important regulator of glucose transport. This inhibitory effect is mediated via gene transcription or protein translation; however, expression of genes potentially involved in GLUT4 trafficking and endocytosis appears not to be involved in these effects.

• Adipocytes
• Adipose tissue
• Calcineurin inhibitors
• Diabetes
• Gene expression
• Glucose uptake

• Single nucleotide polymorphism
• genotyping
• gestational diabetes mellitus

Disturbances of synaptic connectivity during perinatal and adolescent periods have been hypothesized to be related to the pathophysiology of schizophrenia. Rho guanine nucleotide exchange factor 11 (ARHGEF11) is a specific guanine nucleotide exchange factors (GEF) for RhoA, which is a critical regulator of actin cytoskeleton dynamics and organization of dendritic spines and inhibitor of spine maintenance. ARHGEF11 variants are reported to be associated with a higher risk for the onset of schizophrenia in a Japanese population; however, how ARHGEF11 contributes to the pathogenesis of schizophrenia in dendritic spines is unknown. Therefore, we first studied the distribution, binding, and function of ARHGEF11 in the dendritic spines of the rat cerebral cortex. After subcellular fractionation of the rat cerebral cortex, ARHGEF11 was detected with synaptophysin and post-synaptic density protein 95 (PSD-95) in the P2 fractions including synaptosomal fractions containing presynaptic and postsynaptic density proteins. Endogenous ARHGEF11 was coimmunoprecipitated with synaptophysin or PSD-95. In cortical primary neurons at 28 days in vitro, immunostaining revealed that ARHGEF11 located in the dendrites and dendritic spines and colocalized with PSD-95 and synaptophysin. Overexpression of exogenous ARHGEF11 significantly decreased the number of spines (p = 0.008). These results indicate that ARHGEF11 is likely to be associated with synaptic membranes and regulation of spine.

• ARHGEF11
• PSD-95
• dendritic spine
• immunoprecipitation
• schizophrenia
• synaptophysin

Adipose tissue is crucial for the maintenance of energy and metabolic homeostasis and its deregulation can lead to obesity and type II diabetes (T2D). Using gene disruption in the mouse, we discovered a function for a RhoA-specific guanine nucleotide exchange factor PDZ-RhoGEF (Arhgef11) in white adipose tissue biology. While PDZ-RhoGEF was dispensable for a number of RhoA signaling-mediated processes in mouse embryonic fibroblasts, including stress fiber formation and cell migration, it's deletion led to a reduction in their proliferative potential. On a whole organism level, PDZ-RhoGEF deletion resulted in an acute increase in energy expenditure, selectively impaired early adipose tissue development and decreased adiposity in adults. PDZ-RhoGEF-deficient mice were protected from diet-induced obesity and T2D. Mechanistically, PDZ-RhoGEF enhanced insulin/IGF-1 signaling in adipose tissue by controlling ROCK-dependent phosphorylation of the insulin receptor substrate-1 (IRS-1). Our results demonstrate that PDZ-RhoGEF acts as a key determinant of mammalian metabolism and obesity-associated pathologies.

DOI:http://dx.doi.org/10.7554/eLife.06011.001

Obesity is a growing public health concern around the world, and can lead to the development of type 2 diabetes, heart disease and cancer. Both genetics and environmental factors such as diet contribute to obesity. Fat cells are essential to good health, but the excess accumulation of fat cells in obese people involves a complex process that is regulated by interactions between numerous genes, cellular messengers and mechanical forces. Learning more about these factors could help prevent or treat obesity.

One mutation in the gene encoding a protein called PDZ-RhoGEF has been linked to both obesity and type 2 diabetes. People with mutations in this gene are not responsive enough to insulin, a hormone important for sugar metabolism. This can interfere with the body’s ability to burn energy in food or lead to a dangerous build up of sugar in the blood as seen in type 2 diabetes. But exactly what PDZ-RhoGEF normally does to prevent this is unclear.

Chang et al. now show that PDZ-RhoGEF controls fat cell production and the body’s ability to release the energy contained in food. First, mice that had been genetically engineered to lack PDZ-RhoGEF were compared to typical mice. The mice without PDZ-RhoGEF had fewer fat cells than the typical mice, and they burned more energy. The mutant mice walked around about as much as the typical mice but they were more likely to have repetitive movements, the mouse equivalent of human nervous ticks.

Insulin normally stimulates the production of fat cells. But the mutant mice were less able to produce fat cells as they developed into adults. When fed a high fat food diet, the normal mice became fatter and insensitive to insulin and developed other health problems linked to excess fat in the body. The mutant mice on the same diet, however, stayed thin and avoided these health issues. The experiments show that PDZ-RhoGEF helps relay insulin’s message within the body, and as such it plays a critical role in regulating metabolism, sugar levels and fat accumulation. Future work should ask how PDZ-RhoGEF affects other complications linked to obesity, and explore the possibility of developing treatments for obesity based on the biology of this molecule.

DOI:http://dx.doi.org/10.7554/eLife.06011.002

• Rho signaling
• adipose tissue
• cell biology
• developmental biology
• diabetes
• insulin
• mouse
• obesity
• stem cells

• Rho GTP-binding proteins
• Rho guanine nucleotide exchange factors
• angiotensins
• arteries
• hypertension
• leukocytes
• signal transduction

• ARHGEF11
• case-control study
• schizophrenia
• type 2 diabetes mellitus

With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10⁻⁸). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.

• Calcium-Calmodulin-Dependent Protein Kinase Type 1/genetics
• Cation Transport Proteins/genetics
• Cyclin-Dependent Kinase 5/genetics
• Cyclin-Dependent Kinase Inhibitor p15/genetics
• Diabetes Mellitus, Type 2/genetics
• Female
• Genetic Predisposition to Disease/genetics
• Genome-Wide Association Study
• Genotype
• Homeodomain Proteins/genetics
• Humans
• KCNQ1 Potassium Channel/genetics
• Male
• Mexico
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• RNA-Binding Proteins/genetics
• Transcription Factor 7-Like 2 Protein/genetics
• Transcription Factors/genetics
• Zinc Transporter 8
• tRNA Methyltransferases

• K12 DK083021 NIDDK NIH HHS
• 5K12 DK-083021 NIDDK NIH HHS

• Animals
• Biological Transport, Active/genetics
• Cell Movement/genetics
• Cell Proliferation
• Cell Shape/genetics
• Endocrine System Diseases/genetics
• Endocrine System Diseases/metabolism
• Humans
• Monomeric GTP-Binding Proteins/genetics
• Monomeric GTP-Binding Proteins/metabolism
• Protein Processing, Post-Translational/genetics
• Signal Transduction
• Transcription, Genetic/genetics

The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of Rho GTPases and is thought to influence insulin signaling. The R1467H variant of ARHGEF11 has been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) in Western populations.

We investigated the effects of the R1467H variant on susceptibility to T2DM as well as related traits in a Korean population. We genotyped the R1467H (rs945508) of ARHGEF11 in 689 unrelated T2DM patients and 249 non-diabetic individuals and compared the clinical and biochemical characteristics according to different alleles.

The H allele was significantly more frequent in T2DM cases than in controls (P = 0.037, 17.1% and 13.1%; respectively). H homozygocity was associated with a higher risk of T2DM compared to those with R/R or R/H genotype (odds ratio, 5.24; 95% confidence interval, 1.06 to 25.83; P = 0.042). The fasting plasma glucose, HbA1c, fasting insulin, HOMA2-IR and HOMA2-%β levels did not differ significantly between different genotypes.

Our study replicated associations of the ARHGEF11 polymorphism with increased risk of T2DM in a Korean population and thus supports previous data implicating a potential role of ARHGEF11 in the etiology of T2DM. Further studies revealing the underlying mechanism for this association are needed.

• Diabetes mellitus, type 2
• Korean
• Rho guanine nucleotide exchange factor 11
• Single nucleotide polymorphism
• Susceptibility gene

• Adiponectin/blood
• Comorbidity
• Diabetes Mellitus, Type 2/diagnosis
• Diabetes Mellitus, Type 2/genetics
• Diabetes Mellitus, Type 2/metabolism
• Dopamine/genetics
• Dopamine/metabolism
• Endophenotypes
• Genetic Predisposition to Disease
• Genome-Wide Association Study/methods
• Glucose/genetics
• Glucose/metabolism
• Humans
• Risk Factors
• Schizophrenia/diagnosis
• Schizophrenia/genetics
• Schizophrenia/metabolism

• 1R01 MH77852 NIMH NIH HHS

• Adult
• Age of Onset
• Arizona/epidemiology
• Calcium Channels, R-Type/genetics
• Cation Transport Proteins/genetics
• Chromosome Mapping
• Chromosomes, Human, Pair 1
• Diabetes Mellitus, Type 2/epidemiology
• Diabetes Mellitus, Type 2/genetics
• Genetic Linkage
• Genetic Variation
• Humans
• Indians, North American/genetics
• Insulin Resistance/genetics
• Middle Aged
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide

• R01-DK073490 NIDDK NIH HHS
• Intramural NIH HHS

• Chromosome Mapping
• Chromosomes, Human, Pair 1
• Diabetes Mellitus, Type 2/genetics
• Ethnicity/genetics
• Genetic Predisposition to Disease
• Guanine Nucleotide Exchange Factors/genetics
• Humans
• Polymorphism, Single Nucleotide
• Rho Guanine Nucleotide Exchange Factors
• United States

• M01 RR 02719 NCRR NIH HHS
• M01 RR 16500 NCRR NIH HHS
• P30 DK072488 NIDDK NIH HHS
• R01 DK073490 NIDDK NIH HHS
• R01 DK54361 NIDDK NIH HHS
• T32 AG000219 NIA NIH HHS