Department of Diabetes and Cancer Discovery Science, Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope, Duarte, California, United States America.
Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
PLoS One. 2023 Jan 26;18(1):e0280872. doi: 10.1371/journal.pone.0280872. eCollection 2023.
Type 1 diabetes patients carrying a 'protective' insulin gene (INS) variant present a disease endotype with reduced insulin antibody titers, preserved beta cell function and improved glycemic control. We tested whether this protective INS variant associated with lowered risk for development of proliferative diabetic retinopathy (PDR) and diabetic kidney disease (DKD) as long-term diabetic complications. Insulin gene polymorphisms were evaluated in 1,363 type 1 diabetes patients participating in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study that compared intensive versus conventional insulin therapy in relation with development of PDR and DKD with a follow-up of over two decades. PDR and DKD were absent in type 1 diabetes patients carrying the protective INS variant and receiving intensive insulin therapy (the current standard of clinical care) 1-5 years from their diagnosis (n = 67; mean post-diagnosis follow up of 20.4 ± 1.6 years), versus 11 of 258 patients (4.3%) lacking this variant (20.4 ± 1.8 years follow up). In the secondary intervention group of the intensive therapy arm (1-15 years of disease), PDR was significantly less frequent in carriers of the protective INS variant than those without it (4 of 83 [4.8%] vs. 31 of 260 [11.9%]; p = 0.032; 26.1 ± 3.9 and 26.3 ± 4.1 years follow-up, respectively), whereas DKD frequencies were no different between those with or without this variant (5 of 83 [6.0%] vs. 11 of 260 [4.2%]). Carrying a copy of this protective INS variant further reduces the risk of diabetic complications achieved by intensive insulin therapy and marks a disease endotype with superior glycemic control, increased and extended beta cell function, and prevention of DKD and PDR.
1 型糖尿病患者携带一种“保护性”胰岛素基因（INS）变体，其疾病表型表现为胰岛素抗体滴度降低、β细胞功能保存和血糖控制改善。我们检测了这种保护性 INS 变体是否与增殖性糖尿病视网膜病变（PDR）和糖尿病肾病（DKD）等长期糖尿病并发症的发病风险降低相关。在参与糖尿病控制和并发症试验/糖尿病干预和并发症的流行病学（DCCT/EDIC）研究的 1363 名 1 型糖尿病患者中评估了胰岛素基因多态性，该研究比较了强化与常规胰岛素治疗与 PDR 和 DKD 的发展，随访时间超过 20 年。在诊断后 1-5 年（n = 67；平均随访时间 20.4 ± 1.6 年）接受强化胰岛素治疗（目前的临床护理标准）且携带保护性 INS 变体的 1 型糖尿病患者中，PDR 和 DKD 均不存在，而在 258 名未携带该变体的患者中，有 11 名（4.3%）（20.4 ± 1.8 年随访）。在强化治疗组的二次干预亚组（疾病 1-15 年）中，携带保护性 INS 变体的患者 PDR 的发生率明显低于未携带的患者（4 例[4.8%] vs. 31 例[11.9%]；p = 0.032；分别随访 26.1 ± 3.9 年和 26.3 ± 4.1 年），而携带或未携带该变体的患者 DKD 的发生率无差异（5 例[6.0%] vs. 11 例[4.2%]）。携带这种保护性 INS 变体的副本进一步降低了强化胰岛素治疗所达到的糖尿病并发症风险，并标志着一种疾病表型，具有更好的血糖控制、增加和延长的β细胞功能以及预防 DKD 和 PDR。
