Prospective evaluation of glutamine and phospholipids levels in first degree relatives of patients with Type 1 Diabetes from a multiethnic population

A dysregulation in the metabolism of lipids may be an early marker of autoimmunity in Type 1 Diabetes (T1D). It would be of general importance to identify metabolic patterns that would predict the risk for T1D later in life. The aim of this study was to perform a prospective evaluation of glutamine and phospholipids levels in Brazilian first degree relatives (FDR) of patients with T1D in a mean interval of 5 years

Novel enzyme-linked immunosorbent assay for bivalent ZnT8 autoantibodies

Autoantibodies to zinc transporter 8 (ZnT8A) are a powerful diagnostic or predictive marker in type 1 diabetes. However, the widely used current ZnT8A radioligand binding assay (RBA) has proved to be difficult for many laboratories to implement. The aim of this study was the development and characterization of the performance of a novel fluid-phase ZnT8A enzyme-linked immunosorbent assay (ELISA) in relation to standard RBA in type 1 diabetes. Sera from 114 patients with type 1 diabetes and 140 blinded Islet Autoantibody Standardization Program (IASP2012) samples were studied. The sensitivity of ELISA-ZnT8A is equivalent to or slightly higher than that of conventional RBA with similar specificity. Furthermore, the median SD score using this ELISA was significantly higher than that obtained with RBA (P < 0.0001). Multiple logistic regression analysis revealed that ELISA-ZnT8A positivity was associated with younger age of onset (?20 years; OR 15.91, P = 0.0002), acute-onset form of type 1 diabetes (OR 3.38, P = 0.019), and the presence of IA-2 autoantibodies (OR 3.75, P = 0.014). Furthermore, the levels of ELISA-ZnT8A were associated with the reactivity to ZnT8-325Arg, but not ZnT8-325Trp. We conclude that this nonradioactive bivalent ZnT8A assay has high performance and should facilitate large-scale autoantibody screening. Moreover, these results suggest that the humoral autoimmunity against ZnT8 is related to a high risk of faster development of type 1 diabetes and the ZnT8A levels are associated with the known aa325 variants

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10 -6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10 -4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention. © 2014 Nature America, Inc

Loss-of-function mutations in SLC30A8 protect against type 2 diabetes

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10 -6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10 -4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention. © 2014 Nature America, Inc