Low Risk for Diabetic Complications in Type 1 Diabetes Patients Carrying a Protective Insulin Gene Variant

René van Tienhoven, Anh Nguyet Vu, John S. Kaddis, Bart O. Roep.

Abstract

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.

Introduction

There is a growing insight that type 1 diabetes patients and their disease differ [1], even despite receiving the current standard of care to achieve glycemic control. Therefore, a great, and largely unmet, need exists to identity markers and correlates of type 1 diabetes patient subpopulations with differential disease progression, preservation in beta cell function, and glycemic control.

Materials and Methods:

The association between INS variation and the probability of microvascular diabetes complications, proliferative diabetic retinopathy (PDR) and diabetic kidney disease (DKD) was investigated in participants of the Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Following project approval, DCCT/EDIC clinical and SNP study data on 1,441 individuals was downloaded from the National Center for Biotechnology Information database of Genotypes and Phenotypes website.

Discussion:

We conclude that the protective INS variant further decreases the low risk for diabetes complications accomplished through intensive insulin treatment and glycemic control in patients with European ancestry. We propose that the combination of immune tolerance to insulin and preserved beta cell function in patients carrying the protective INS variant contributes to superior glycemic control previously reported in carriers with recent onset pediatric T1D, thereby reducing the risk of development of diabetic complications.

Acknowledgments:

The authors thank Z. Chen and R. Natarajan for their advice in defining PDR and DKD.

Citation: van Tienhoven R, Vu AN, Kaddis JS, Roep BO (2023) Low risk for diabetic complications in type 1 diabetes patients carrying a protective insulin gene variant. PLoS ONE 18(1): e0280872. https://doi.org/10.1371/journal.pone.0280872

Editor: Matthias G. von Herrath, La Jolla Institute for Allergy and Immunology, UNITED STATES

Received: October 7, 2022; Accepted: January 10, 2023; Published: January 26, 2023.

Copyright: © 2023 van Tienhoven et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The Diabetes Control and Complications Trial and Epidemiology of Diabetes Interventions and Complications Study dataset is available at the National Center for Biotechnology Information database of Genotypes and Phenotypes, under accession number phs000086.v3.p1.

Funding: This study was supported by the Wanek Family Project for Type 1 Diabetes (Director: BOR).

Competing interests: The authors have declared that no competing interests exist.