Peripheral Blood Monocyte Gene Expression Profile Clinically Stratifies Patients With Recent-Onset Type 1 Diabetes

Katharine M. Irvine,1 Patricia Gallego,2,3 Xiaoyu An,1 Shannon E. Best,1 Gethin Thomas,1 Christine Wells,4 Mark Harris,2 Andrew Cotterill,2 and Ranjeny Thomas1

Abstract

Novel biomarkers of disease progression after type 1 diabetes onset are needed. We profiled peripheral blood (PB) monocyte gene expression in six healthy subjects and 16 children with type 1 diabetes diagnosed ∼3 months previously and analyzed clinical features from diagnosis to 1 year. Monocyte expression profiles clustered into two distinct subgroups, representing mild and severe deviation from healthy control subjects, along the same continuum. Patients with strongly divergent monocyte gene expression had significantly higher insulin dose–adjusted HbA1c levels during the first year, compared with patients with mild deviation. The diabetes-associated expression signature identified multiple perturbations in pathways controlling cellular metabolism and survival, including endoplasmic reticulum and oxidative stress (e.g., induction of HIF1A, DDIT3, DDIT4, and GRP78). Quantitative PCR (qPCR) of a 9-gene panel correlated with glycemic control in 12 additional recent-onset patients. The qPCR signature was also detected in PB from healthy first-degree relatives. A PB gene expression signature correlates with glycemic control in the first year after diabetes diagnosis and is present in at-risk subjects. These findings implicate monocyte phenotype as a candidate biomarker for disease progression pre- and postonset and systemic stresses as contributors to innate immune function in type 1 diabetes.

The most promising stage for therapeutic intervention in type 1 diabetes is presently at diagnosis, with the goal of prolonging remission and preserving residual β-cell mass. However, the rate of type 1 diabetes progression is heterogeneous and unpredictable. The quality of glycemic control in early disease has far-reaching implications for disease progression and the development of diabetes complications (1). Younger age, presentation with diabetic ketoacidosis, a history of viral infection, or low adiponectin (a marker of insulin resistance) have been associated with a low frequency of remission (2–4), but no biomarkers offering insight into the immunological basis of disease progression have so far been identified. Such biomarkers would also assist trial design. For example, immunotherapies in recent trials temporarily delayed disease progression, but treated patients eventually deteriorated on a similar trajectory to control subjects (5).

The versatile cells of the innate immune system, including peripheral blood (PB) monocytes and their differentiated tissue progeny, macrophages, and dendritic cells (DCs), are powerful sensors of stress and danger and mediators of tissue repair. In their role as antigen presenting cells, they orchestrate adaptive immune responses to both endogenous and pathogen-mediated host damage. Paradoxically, innate immune activation may play both pathological and protective roles in type 1 diabetes, depending on disease stage and context (6). At a molecular level, there is substantial evidence for dysregulated innate immunity in type 1 diabetes (7–10), both before and after disease onset. Activated macrophages and DCs are observed in rodent pancreatic islets before lymphocyte recruitment and are thought to be the primary source of the proinflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-6, and IL-1β that are implicated in type 1 diabetes pathogenesis (11). Macrophages are also found in islets from recent-onset type 1 diabetic patients (12). In contrast with their proinflammatory roles, macrophages also have immunoregulatory and tissue repair roles, which may be critical in restraining β-cell destruction. Diabetes was exacerbated in mice that lack colony stimulating factor (CSF)-1–dependent pancreatic macrophages, whereas macrophages promoted β-cell survival and function in a CSF-1–dependent manner (13,14).

We hypothesized that PB monocyte phenotype and function constitute sensitive indicators of the prodiabetes microenvironment, making them ideal biomarkers of innate immune status in type 1 diabetes. Previous PB screening approaches identified proinflammatory signatures, although these studies were in mixed cell populations and were frequently complicated by the proinflammatory effects of hyperglycemia (8,9). We characterized monocyte gene expression in insulin-treated type 1 diabetic patients 3 months after disease onset and analyzed clinical features from diagnosis to 1 year. We report a PB monocyte expression profile, which clinically stratifies glycemic control within the first year after type 1 diabetes diagnosis.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331753/