A pancreatic β-cell-specific homolog of glucose-6-phosphatase emerges as a major target of cell-mediated autoimmunity in diabetes

Diabetes has been termed the epidemic of the 21st century and over the past 50 years in Western societies has been doubling in incidence every 15 years. It exacts a huge socioeconomic toll because of its devastating microvascular and macrovascular complications and the need of patients to maintain a lifetime daily therapeutic regimen. The childhood-onset form of diabetes, which accounts for 10% of all cases in humans [autoimmune or type 1 diabetes (IDDM)], is the product of a T lymphocyte-dependent autoimmune process that specifically destroys the insulin-secreting β cells of the pancreas without affecting contiguous endocrine cells or the surrounding exocrine tissue (1). Such tissue and cell specificity might logically be the product of an autoimmune reactivity directed at β-cell-specific molecular targets mediated by direct cellular contact between the target β cell and effector cytotoxic T lymphocytes. The article by Lieberman et al. (2) in a recent issue of PNAS supports such a notion and identifies the molecular target of a diabetogenic CD8 T cell in diabetes-susceptible nonobese diabetic (NOD) mice as the β-cell-specific protein islet glucose-6-phosphatase (G6Pase) catalytic subunit-related protein (IGRP). Moreover, it shows on the basis of T cell antigen receptor (TCR) Vα-chain usage that the TCR usage of the T cells studied in these experiments represents a dominant specificity in the NOD mouse, and that such cells are the major component of the CD8 T cell population infiltrating the islet up to the onset of diabetes (3).

Type 1 diabetes is a polygenic disorder both in humans and in the NOD mouse involving ≥20 loci (4) but with a major contribution to susceptibility from the MHC class II region (up to 50% in humans). The only other alleles un-equivocally identified lie within the variable number tandem repeat region of the insulin gene (IDDM2) and CTLA-4 (IDDM12) …