Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era

Abstract

Type 1 diabetes affects millions of people globally and requires careful management to avoid serious long-term complications, including heart and kidney disease, stroke, and loss of sight. The type 1 diabetes patient cohort is highly heterogeneous, with individuals presenting with disease at different stages and severities, arising from distinct etiologies, and overlaying varied genetic backgrounds. At present, the "one-size-fits-all" treatment for type 1 diabetes is exogenic insulin substitution therapy, but this approach fails to achieve optimal blood glucose control in many individuals. With advances in our understanding of early-stage diabetes development, diabetes stratification, and the role of genetics, type 1 diabetes is a promising candidate for a personalized medicine approach, which aims to apply "the right therapy at the right time, to the right patient". In the case of type 1 diabetes, great efforts are now being focused on risk stratification for diabetes development to enable pre-clinical detection, and the application of treatments such as gene therapy, to prevent pancreatic destruction in a sub-set of patients. Alongside this, breakthroughs in stem cell therapies hold great promise for the regeneration of pancreatic tissues in some individuals. Here we review the recent initiatives in the field of personalized medicine for type 1 diabetes, including the latest discoveries in stem cell and gene therapy for the disease, and current obstacles that must be overcome before the dream of personalized medicine for all type 1 diabetes patients can be realized.

Keywords: Autoimmunity; Gene polymorphism; Gene therapy; Genomic Risk Score; Insulin therapy; Pancreatic β cells; Personalized medicine; Personalized treatment; Stem cells; Type 1 diabetes.

Fig. 1

Environmental factors associated with initiation of, or protection from islet autoimmunity (IA) and progression to T1D. Adopted with permission from (Craig et al. 2019)

Fig. 2

Development and staging of type 1 diabetes. T1D is characterized by a gradual loss of β-cell function (black dashed-dotted line) over time. As the disease progresses, beta cell function falls below the threshold required to maintain glucose control creating a requirement for insulin replacement therapy. Genetic and environmental risk are both included in the disease etiology. In stage 1, β-cell autoantibodies are persistent, but normoglycemia remains and there are no clinical symptoms. Throughout stage 2, the number of β-cell autoantibodies may induce dysglycemia but still without any diabetes symptoms. In stage 3, β-cell autoantibodies are predominant and clear symptoms of diabetes have emerged. In the white boxes are categories of biomarkers which could be leveraged to refine the staging paradigm, improve prognostic predictions, or subset individuals within a given stage of disease [38]. The specifics of these biomarkers are discussed in the text related to the relevant stage. The staging of T1D pathogenesis was proposed by Insel et al. [36] and the figure explanation was adapted from the same publication on addition to [36]© 2015 The American Diabetes Association

Fig. 3

How genes are delivered to the human body during gene therapy approaches. Gene therapy have utilized two major approaches for transferring therapeutic transgenes into recipients 'body. First approach, is by direct infusion of the therapeutic gene into human body through a vehicle. Altered viruses often used for delivering the gene into specific human cell types. This method is inexact as it is limited to specific cell types that the viral vehicle can infect. Nonviral vehicles for directly delivering genes into cells are also being explored, including the use of plain DNA and DNA wrapped in a coat of fatty molecules known as liposomes. Th second approach utilize a living cells to transfer the therapeutic transgenes into recipients 'body. The transferring cells often a type of stem cell that removed from the body, and the therapeutic transgene is presented to them through direct transfer method. The genetically altered cells then grow and multiply before infused back to the recipient