TYK2 Promoter Variant Is Associated with Impaired Insulin Secretion and Lower Insulin Resistance in Japanese Type 2 Diabetes Patients

Abstract

Accumulating evidence has suggested that viral infection causes type 1 diabetes due to direct β-cell damage and the triggering of autoimmune reactivity to β cells. Here, we elucidated that the tyrosine kinase 2 <i>(Tyk2</i>) gene, encoding an interferon receptor signaling molecule, is responsible for virus-induced diabetes in mice, and its promoter variant confers a risk of type 1 diabetes in humans. This study investigated the relationship between a <i>TYK2</i> promoter variant <i>(TYK2PV)</i> and insulin secretion in type 2 diabetes patients. <i>TYK2PV</i> status was determined using direct DNA sequencing and its associations with fasting insulin, C-peptide, and homeostatic model assessment of insulin resistance (HOMA-IR) were evaluated in type 2 diabetes patients without sulfonylurea or insulin medication. Of the 172 patients assessed, 18 (10.5%) showed <i>TYK2PV</i>-positivity. Their body mass index (BMI) was significantly lower than in those without the variant (23.4 vs. 25.4 kg/m², <i>p</i> = 0.025). Fasting insulin (3.9 vs. 6.2 μIU/mL, <i>p</i> = 0.007), C-peptide (1.37 vs. 1.76 ng/mL, <i>p</i> = 0.008), and HOMA-IR (1.39 vs. 2.05, <i>p</i> = 0.006) were lower in those with than in those without the variant. Multivariable analysis identified that <i>TYK2PV</i> was associated with fasting insulin ≤ 5 μIU/mL (odds ratio (OR) 3.63, <i>p</i> = 0.025) and C-peptide ≤ 1.0 ng/mL (OR 3.61, <i>p</i> = 0.028), and also lower insulin resistance (HOMA-IR ≤ 2.5; OR 8.60, <i>p</i> = 0.042). <i>TYK2PV</i> is associated with impaired insulin secretion and low insulin resistance in type 2 diabetes. Type 2 diabetes patients with <i>TYK2PV</i> should be carefully followed in order to receive the appropriate treatment including insulin injections.