A central role for GRB10 in regulation of islet function in man.

Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

Genetics of diabetes complications.

Chronic hyperglycemia and duration of diabetes are the major risk factors associated with development of micro- and macrovascular complications of diabetes. Although it is believed that hyperglycemia induces damage to the particular cell subtypes, e.g., mesangial cells in the renal glomerulus, capillary endothelial cells in the retina, and neurons and Schwann cells in peripheral nerves, the exact mechanisms underlying these damaging defects are not yet well understood. Clustering of micro- and macrovascular complications in families of patients with diabetes suggests a strong genetic susceptibility. However, until now only a handful number of genetic variants were reported to be associated with either nephropathy (ACE, ELMO1, FRMD3, and AKR1B1) or retinopathy (VEGF, AKR1B1, and EPO), and only a few studies were carried out for genetic susceptibility to cardiovascular diseases (ADIPOQ, GLUL) in patients with diabetes. It is, therefore, obvious that the accumulation of more data from larger studies and better phenotypically characterized cohorts is needed to facilitate genetic discoveries and unravel novel insights into the pathogenesis of diabetic complications.

Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population.

Phosphatidylinositol-specific phospholipase C X domain 3 (PLCXD3) has been shown to influence pancreatic ß-cell function by disrupting insulin signaling. Herein, we investigated two genetic variants in the PLCXD3 gene in relation to type 2 diabetes (T2D) or metabolic syndrome (MetS) in the Emirati population. In total, 556 adult Emirati individuals (306 T2D and 256 controls) were genotyped for two PLCXD3 variants (rs319013 and rs9292806) using TaqMan genotyping assays. The frequency distribution of minor homozygous CC genotype of rs9292806 and GG genotype of rs319013 were significantly higher in subjects with MetS compared to Non-MetS (p < 0.01). The minor homozygous rs9292806-CC and rs319013-GG genotypes were significantly associated with increased risk of MetS (adj. OR 2.92; 95% CI 1.61-5.3; p < 0.001) (adj. OR 2.62; 95% CI 1.42-4.83; p = 0.002), respectively. However, no associations were detected with T2D. In healthy participants, the homozygous minor genotypes of both rs9292806 and rs319013 were significantly higher fasting glucose (adj. p < 0.005), HbA1c (adj. p < 0.005) and lower HDL-cholesterol (adj. p < 0.05) levels. Data from T2D Knowledge Portal database disclosed a nominal association of rs319013 and rs9292806 with T2D and components of MetS. Bioinformatics prediction analysis showed a deleterious effect of rs9292806 on the regulatory regions of PLCXD3. In conclusion, this study identifies rs319013 and rs9292806 variants of PLCXD3 as additional risk factors for MetS in the Emirati population.

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone with extrapancreatic effects beyond glycemic control. Here we demonstrate unexpected effects of GIP signaling in the vasculature. GIP induces the expression of the proatherogenic cytokine osteopontin (OPN) in mouse arteries via local release of endothelin-1 and activation of CREB. Infusion of GIP increases plasma OPN concentrations in healthy individuals. Plasma endothelin-1 and OPN concentrations are positively correlated in patients with critical limb ischemia. Fasting GIP concentrations are higher in individuals with a history of cardiovascular disease (myocardial infarction, stroke) when compared with control subjects. GIP receptor (GIPR) and OPN mRNA levels are higher in carotid endarterectomies from patients with symptoms (stroke, transient ischemic attacks, amaurosis fugax) than in asymptomatic patients, and expression associates with parameters that are characteristic of unstable and inflammatory plaques (increased lipid accumulation, macrophage infiltration, and reduced smooth muscle cell content). While GIPR expression is predominantly endothelial in healthy arteries from humans, mice, rats, and pigs, remarkable upregulation is observed in endothelial and smooth muscle cells upon culture conditions, yielding a "vascular disease-like" phenotype. Moreover, the common variant rs10423928 in the GIPR gene is associated with increased risk of stroke in patients with type 2 diabetes.

Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.

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.