GDF15: a potential therapeutic target for type 1 diabetes

Abstract

Introduction: Current treatment for type 1 diabetes (T1D) is centered around insulin supplementation to manage the effects of pancreatic β cell loss. GDF15 is a potential preventative therapy against T1D progression that could work to curb increasing disease incidence.

Areas covered: This paper discusses the known actions of GDF15, a pleiotropic protein with metabolic, feeding, and immunomodulatory effects, connecting them to highlight the open opportunities for future research. The role of GDF15 in the prevention of insulitis and protection of pancreatic β cells against pro-inflammatory cytokine-mediated cellular stress are examined and the pharmacological promise of GDF15 and critical areas of future research are discussed.

Expert opinion: GDF15 shows promise as a potential intervention but requires further development. Preclinical studies have shown poor efficacy, but this result may be confounded by the measurement of gross GDF15 instead of the active form. Additionally, the effect of GDF15 in the induction of anorexia and nausea-like behavior and short-half-life present significant challenges to its deployment, but a systems pharmacology approach paired with chronotherapy may provide a possible solution to therapy for this currently unpreventable disease.

Keywords: ER stress; GDF15; immunomodulator & chronotherapy; insulitis; type 1 diabetes (T1D); type 2 diabetes (T2D); β cells stress.

Figure 1.. Trends of published research articles related to GDF15.

A. represents the distribution of GDF15 research articles published since 1997. B. represents the number of GDF15 research articles arranged according to the topics (CNS: central nervous system, T2D: type 2 diabetes, T1D: type 1 diabetes). The articles containing titles with GDF15 or its aliases (i.e., MIC-1, NAG-1, PTGFB, PALB, & NRG1) were curated using the PubMed search tool, specifically excluding reviews, meta-analysis, commentary, & corrections in our analysis.

Figure 2.. Regulators and effectors of GDF15.

GDF15 is expressed in most human tissues in response to various signals, including tissue damage, hypoxia, mechanical compression and many more. The protein biosynthesis of GDF15 is well-documented and includes pro-GDF15 dimer and mature GDF15 synthesis. It is still not very clear which of these protein forms are functionally relevant as they both are secreted in the plasma. Once released, they have a plethora of effectors, which can be broadly classified as defined and undefined mechanisms. Under defined mechanisms, GDF15 has been shown to interact with 3 distinct receptors i.e., GFRAL, ErbB2 and CD44, which have been reported to have different effects. In addition, there exists a large number of undefined correlational effects of GDF15, which could be the result of either direct or indirect mechanisms.

Figure 3.. Schematic representing the stages of T1D and the potential GDF15 therapeutic roles.

T1D is divided into 3 main stages and one pre-stage 1. The pre-stage 1 is marked by HLA genotype which gets triggered by an insult, such as viral infection, β cell stress or both. This initiates immune activation and response, leading to increased β cell stress and hyper HLA expression. Eventually, these events initiate pro-apoptotic signals and cause loss of β cell mass. GDF15 is an established biomarker for T1D and has been shown to reduce T1D insulitis. The potential roles of GDF15 in preventing or slowing the progression of T1D could be a combination of anti-β cell stress, immunomodulatory effect, management of metabolic stress and finally, restoration of glycemic control. Overall, GDF15 has the potential to be developed as a preventative therapy for pre-stage 1 to stage 2, or a concomitant therapy along with insulin to reduce the progression of the disease in the later stages.