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Diabetes diagnosed in adults is a highly heterogeneous disorder. It mostly consists of what is referred to as type 2 diabetes but also comprises other entities (i.e. different diseases), including latent autoimmune diabetes, late onset forms of monogenic diabetes and familial diabetes of the adulthood, which has recently been the source of new diabetogenes discovery. Notably, type 2 diabetes is itself heterogeneous as it includes subtypes with onset at the extremes of age and/or weight distributions characterized by different degree of hyperglycemia and cardiovascular risk as compared to common forms of type 2 diabetes occurring in middle-aged, overweight/obese individuals. Understanding whether these are different presentations of one, highly heterogeneous disease or separate nosological entities with different clinical trajectories and requiring different treatments is essential to effectively pursue the path of precision medicine. [ABSTRACT FROM AUTHOR]

We present an atypical association of SCN2A epileptic encephalopathy with severe cortical dysplasia. SCN2A mutations are associated with epileptic syndromes from benign to extremely severe in absence of such macroscopic brain findings. Prenatal MRI (Magnetic Resonance Imaging) in a 32 weeks fetus, with US (Ultrasonography) diagnosis of isolated ventriculomegaly showed CNS (Central Nervous System) dysplasia characterized by lack of differentiation between cortical and subcortical layers, pachygyria and corpus callosum dysgenesis. Postnatal MRI confirmed the prenatal findings. On day 6 the baby presented a focal status epilepticus, partially controlled by phenobarbital, phenytoin, and levetiracetam. After three weeks a moderate improvement in seizure control has been achieved with carbamazepine. Exome sequencing detected a de novo heterozygous mutation in the SCN2A gene, encoding the α II -subunit of a sodium channel. The patient findings expand the phenotype spectrum of SCN2A mutations to epileptic encephalopathies with macroscopic brain developmental features. [ABSTRACT FROM AUTHOR]

Objective Genes that modulate insulin sensitivity may also be involved in shaping the risk of coronary artery disease (CAD). The relatively common TRIB3 Q84R polymorphism (rs2295490) has been associated with abnormal insulin signaling, endothelial dysfunction, insulin resistance, and pro-atherogenic phenotypes. The aim of our study was to investigate the association between low-frequency TRIB3 coding variants and CAD in patients with type 2 diabetes (T2D). Methods Three case–control studies for CAD from Italy and US were analyzed, for a total of 1565 individuals, all with type 2 diabetes. Infrequent variants were identified by re-sequencing TRIB3 exons in 140 “extreme cases” and 140 “super-controls” and then genotyped in all study subjects. Results TRIB3 infrequent variants (n = 8), considered according to a collapsing rare variants framework, were significantly associated with CAD in diabetic patients from Italy (n = 700, OR = 0.43, 95% CI 0.20–0.91; p = 0.027), but not from the US (n = 865, OR = 1.22, 95% CI 0.69–2.18; p = 0.49). In the Italian sets, the association was especially strong among individuals who also carried the common R84 variant. Conclusion Although preliminary, our finding suggests a role of TRIB3 low-frequency variants on CAD among Italian patients with T2D. Further studies are needed to address the role of TRIB3 infrequent variants in other populations of both European and non-European ancestries. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). Conclusions: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies. [Copyright &y& Elsevier]

Abstract: Objective: Obesity and cardiovascular disease recognize a common metabolic soil and may therefore share part of their genetic background. Genome-wide association studies have identified variability at the SH2B1 locus as a predictor of obesity. We investigated whether SNP rs4788102, which captures the entire SH2B1 variability, is associated with coronary artery disease (CAD) and/or myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). Design and setting: SNP rs4788102 was typed in 2015 White subjects with T2DM from three CAD case–control studies [n =740 from the Gargano Hearth Study (GHS, Italy); n =818 from the Joslin Hearth Study (JHS, Boston); n =457 from the University of Catanzaro (CZ, Italy)]. Results: SNP rs4788102 (G/A) was not associated with CAD (overall allelic OR=1.06, 95% CI=0.93–1.21; p =0.37). On the contrary, it was associated with MI in GHS (1.42, 1.12–1.81; p =0.004) and in the three samples analyzed together (1.21, 1.04–1.41; p =0.016). Insulin stimulated nitric oxide synthase (NOS) activity in human vein endothelial cells from G/G (n =4, p =0.03) but not the G/A (n =5, p =0.83) genotype. Of the SNPs in perfect LD with rs4788102, one (rs7498665) affects amino acid polarity (Ala484Thr) and falls into a highly conserved protein segment of SH2B1 containing a class II SH3 domain binding site. Conclusions: Variability at the SH2B1 obesity locus is associated with MI in diabetic patients and with reduced insulin-stimulated NOS activity in human endothelial cells. Further studies are needed to replicate this association and dissect the biology underlying this finding. [Copyright &y& Elsevier]

Abstract: Objective: SNP rs2943641 near the insulin receptor substrate 1 (IRS1) gene has been found to be associated with type 2 diabetes (T2D) and insulin-resistance in genome-wide association studies. We investigated whether this SNP is associated with cardiovascular risk factors and coronary artery disease (CAD) among diabetic individuals. Methods: SNP rs2943641 was typed in 2133 White T2D subjects and tested for association with BMI, serum HDL cholesterol and triglycerides, hypertension history, and CAD risk. Results: HDL cholesterol decreased by 1mg/dl (p =0.004) and serum triglycerides increased by 6mg/dl (p =0.016) for each copy of the insulin-resistance allele. Despite these effects, no association was found with increased CAD risk (OR=1.00, 95% CI 0.88–1.13). Conclusions: The insulin-resistance and T2D locus near the IRS1 gene is a determinant of lower HDL cholesterol among T2D subjects. However, this effect is small and does not translate into a detectable increase in CAD risk in this population. [Copyright &y& Elsevier]