CD38 autoimmunity: recent advances and relevance to human diabetes.
Human CD38 is a protein which catalyzes the synthesis of nicotinic acid adenine dinucleotide (NAADP+) and the conversion of NAD+ to cADPR. Both cADPR and NAADP+ are powerful intracellular Ca2+ ([Ca2+]i) mobilizers in different cell types. Recently, the presence of CD38 autoantibodies has been found in a significant number (9-15%) of patients with Type 2 or long-standing Type 1 diabetes. These autoantibodies are biologically active, the majority of them (-60%) displaying agonistic properties, i.e., [Ca2+]i mobilization in lymphocytic cell lines and in pancreatic islets. In cultured rat pancreatic islets, the human autoantibodies inhibit glucose-induced insulin release, whereas, in human pancreatic islets CD38 autoantibodies stimulate glucose-mediated insulin secretion. The clinical phenotype of anti-CD38-positive Type 2 diabetes differs from the LADA (latent autoimmune diabetes of adults) phenotype. When accurately matched for age and obesity, only LADA patients with anti-GAD antibodies, but not GAD-negative/ CD38-positive patients, have reduced in vivo beta-cell function in comparison to antibody-negative patients. Transgenic mice overexpressing CD38 show enhanced glucose-induced insulin release, whereas, conversely, CD38 knockout mice display a severe impairment in beta-cell function. Few Japanese diabetic patients carry a missense mutation in the CD38 gene; in Caucasian patients mutations in the CD38 gene have not been found. Collectively, these findings suggest that activation of CD38 represents an alternative signaling pathway for glucose-induced insulin secretion in human beta-cells. More information, however, is necessary to gauge the role of CD38 autoimmunity in the context of the natural history of human Type 1 or Type 2 diabetes.
Antonelli
A
A
Metabolism Unit, Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy. a.antonelli@med.unipi.it
Ferrannini
E
E
D036541:ADP-ribosyl Cyclase / Q000235:genetics / Q000276:immunology*; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000032:analysis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008214:Lymphocytes / Q000276:immunology; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015398:Signal Transduction
D015703:Antigens, CD; D001323:Autoantibodies; D007004:Hypoglycemic Agents; D007328:Insulin; D008562:Membrane Glycoproteins; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1