Possible heterogeneity of initial pancreatic islet beta‐cell autoimmunity heralding type 1 diabetes

Abstract

The etiology of type 1 diabetes (T1D) foreshadows the pancreatic islet beta‐cell autoimmune pathogenesis that heralds the clinical onset of T1D. Standardized and harmonized tests of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen‐2 (IA‐2A), and ZnT8 transporter (ZnT8A) allowed children to be followed from birth until the appearance of a first islet autoantibody. In the Environmental Determinants of Diabetes in the Young (TEDDY) study, a multicenter (Finland, Germany, Sweden, and the United States) observational study, children were identified at birth for the T1D high‐risk HLA haploid genotypes DQ2/DQ8, DQ2/DQ2, DQ8/DQ8, and DQ4/DQ8. The TEDDY study was preceded by smaller studies in Finland, Germany, Colorado, Washington, and Sweden. The aims were to follow children at increased genetic risk to identify environmental factors that trigger the first‐appearing autoantibody (etiology) and progress to T1D (pathogenesis). The larger TEDDY study found that the incidence rate of the first‐appearing autoantibody was split into two patterns. IAA first peaked already during the first year of life and tapered off by 3–4 years of age. GADA first appeared by 2–3 years of age to reach a plateau by about 4 years. Prior to the first‐appearing autoantibody, genetic variants were either common or unique to either pattern. A split was also observed in whole blood transcriptomics, metabolomics, dietary factors, and exposures such as gestational life events and early infections associated with prolonged shedding of virus. An innate immune reaction prior to the adaptive response cannot be excluded. Clarifying the mechanisms by which autoimmunity is triggered to either insulin or GAD65 is key to uncovering the etiology of autoimmune T1D.

Childhood screening for type 1 diabetes comparing automated multiplex Antibody Detection by Agglutination-PCR (ADAP) with single plex islet autoantibody radiobinding assays

“… 3 , 4 , 5 The etiology of type 1 diabetes may involve environmental exposures that precede the appearance of a first autoantibody against either insulin (IAA) or glutamic acid decarboxylase (GADA). 6 The subsequent pathogenesis is marked by IAA, GADA, or both, in addition to autoantibodies against islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). 2 , 7 Two or more of these islet autoantibodies represent stage 1 (normal blood glucose) or stage 2 (abnormal glucose tolerance) type 1 diabetes.…”

A Bioartificial Pancreas with “Immune Stealth” and Continuous Oxygen Supply for Islet Transplantation

“…Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the selective destruction of the insulin‐producing β‐cells in the pancreatic islets and subsequently an absolute deficiency of insulin, which leads to significant hyperglycemia. [ 1,2 ] Exogenous insulin treatment stands as the paramount approach for T1DM therapy, serving as the critical remedy essential for the survival of T1DM patients. [ 3 ] A hybrid “closed‐loop” system has recently been developed to manage blood glucose levels, which automatically senses blood glucose through a continuous glucose monitoring sensor and drives a body worn insulin pump to deliver insulin to the body.…”

A multi-ancestry genome-wide association study in type 1 diabetes

“…Type 1 diabetes is a common autoimmune disease in which the destruction of pancreatic β-cells results in the eventual inability of the body to produce insulin [1][2][3][4]. Without insulin, there is accumulation of glucose in the bloodstream and an inability for glucose to enter cells for production of energy.…”