More than a decade after the discovery of a novel type 1 diabetes risk locus on chromosome 16p13, there remains complexity and controversy over the specific gene(s) that regulate diabetes pathogenesis.A new study by Nieves-Bonilla et al. shows that one of these genes, DEXI, is unlikely to contribute to type 1 diabetes pathogenesis and positions the endolysosomal E3 ubiquitin ligase CLEC16A as the primary culprit by which this gene locus influences diabetes risk.
In addition to type 1 diabetes high-risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype, the possibility that the risk variants of BACH2 and CLEC16A could contribute to the development of insulin-triggered type 1 diabetescannot be excluded.
Inhibition of the Clec16a pathway by the chemotherapeutic lenalidomide, a selective ubiquitin ligase inhibitor associated with new-onset diabetes, impairs β-cell mitophagy, oxygen consumption, and insulin secretion.
This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases.
The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that three different polymorphisms were significantly (P<0.005) associated with the prevalence of MI in individuals with or without hypertension or diabetes mellitus: the C --> T polymorphism of CLEC16A (rs9925481) in individuals without hypertension, the A --> G polymorphism of SEMA3F (rs12632110) in individuals without diabetes mellitus and the A --> G polymorphism of ALOX5 (rs7913948) in individuals without hypertension or diabetes mellitus.