1706-P: A Promoter Variant of TYK2, a Putative Virus-Induced Susceptibility Gene, Is Associated with Impaired Insulin Secretion and Nonobese Type 2 Diabetes

Background: Type 2 diabetes mellitus is typically associated with obesity and insulin resistance. It is well known that viral infection triggers type 1 diabetes, but a potential link with type 2 diabetes has not been fully established. We have reported that a natural mutation in the tyrosine kinase 2 (TYK2) gene, which encodes an interferon receptor signaling molecule, is responsible for encephalomyocarditis (EMC) virus-induced diabetes in mice (Nat Commun 2015). Moreover, a human TYK2 promoter variant (TYK2PV) (NCBI ClinVer ID:440728) is associated with higher risks of not only type 1, but also type 2 diabetes (EBioMedicine 2015). Therefore, we hypothesized that impaired insulin secretion associated with TYK2PV causes type 2 diabetes. Here, we studied the relationships between TYK2PV, and insulin secretion and obesity in patients with type 2 diabetes. Methods: The presence of TYK2PV was determined using direct sequencing, and insulin secretion was evaluated, in type 2 diabetes patients who were not administering either sulfonylureas or insulin. Results: Of the 173 patients assessed, 18 (10.4%) were TYK2PV-positive, and their median BMI was significantly lower than those without the variant (25.3 vs. 23.4 kg/m2, p=0.029). Moreover, the HOMA-β (19.1 vs. 30.0, p=0.027) and fasting serum insulin (3.91 vs. 6.16 μIU/mL, p=0.007) were lower in patients with TYK2PV than in those without. Multivariable analysis showed that TYK2PV was significantly associated with fasting insulin <5μIU/ml (odds ratio 4.14, 95% confidence interval 1.404-12.21, p=0.021). Conclusions: TYK2PV is associated with lower insulin secretion in type 2 diabetes, consistent with it being a virus-induced diabetes susceptibility gene. Therefore, type 2 diabetes patients with TYK2PV should be carefully followed, so that they receive the most appropriate treatment, including insulin.