Cell type-specific immune phenotypes predict loss of insulin secretion in new-onset type 1 diabetes

JCI Insight. 2019 Feb 21;4(4):e125556. doi: 10.1172/jci.insight.125556.


The rate of decline in insulin secretion after diagnosis with type 1 diabetes (T1D) varies substantially among individuals and with age at diagnosis, but the mechanism(s) behind this heterogeneity are not well understood. We investigated the loss of pancreatic β cell function in new-onset T1D subjects using unbiased whole blood RNA-seq and verified key findings by targeted cell count measurements. We found that patients who lost insulin secretion more rapidly had immune phenotypes ("immunotypes") characterized by higher levels of B cells and lower levels of neutrophils, especially neutrophils expressing primary granule genes. The B cell and neutrophil immunotypes showed strong age dependence, with B cell levels in particular predicting rate of progression in young subjects only. This age relationship suggested that therapy targeting B cells in T1D would be most effective in young subjects with high pretreatment B cell levels, a prediction which was supported by data from a clinical trial of rituximab in new-onset subjects. These findings demonstrate a link between age-related immunotypes and disease outcome in new-onset T1D. Furthermore, our data suggest that greater success could be achieved by targeted use of immunomodulatory therapy in specific T1D populations defined by age and immune characteristics.

Keywords: Autoimmunity; Bioinformatics; Diabetes; Immunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Child
  • Controlled Clinical Trials as Topic
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / immunology*
  • Disease Progression
  • Female
  • Humans
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use*
  • Insulin / metabolism
  • Insulin Secretion / drug effects
  • Insulin Secretion / immunology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Leukocyte Count
  • Leukocytes / drug effects
  • Leukocytes / immunology*
  • Male
  • Middle Aged
  • Patient Selection
  • Prognosis
  • RNA-Seq
  • Treatment Outcome
  • Young Adult


  • Immunologic Factors
  • Insulin