Low risk for diabetic complications in type 1 diabetes patients carrying a protective insulin gene variant

• Published in: PloS one 2023-01, Vol.18 (1), p.e0280872-e0280872
• Main Authors: van Tienhoven, René, Vu, Anh Nguyet, Kaddis, John S, Roep, Bart O
• Format: Article
• Language: English
• Subjects: Antibodies; Beta cells; Biology and Life Sciences; Blood Glucose - metabolism; Care and treatment; Comparative analysis; Complications; Complications and side effects; Development and progression; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - genetics; Diabetes therapy; Diabetic nephropathies; Diabetic retinopathy; Diabetic Retinopathy - diagnosis; Diagnosis; Disease control; Disease prevention; Epidemiology; Gene polymorphism; Genes; Genetic aspects; Genetic polymorphisms; Genetic variation; Glycated Hemoglobin; Health risk assessment; Health risks; Humans; Insulin; Insulin - therapeutic use; Insulin, Regular, Human - therapeutic use; Intervention; Kidney diseases; Medicine and Health Sciences; Patients; Pediatrics; Prevention; Retinopathy; Risk; Risk factors; Statistical significance; Statistics; Therapy; Type 1 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0280872

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.