Disruption of intestinal motility by a calcium channel-stimulating autoantibody in type 1 diabetes.
OBJECTIVE
Autonomic neuropathy, including gastrointestinal dysfunction, is a common complication of type 1 diabetes; however, its cause is uncertain. This study aimed to test whether functional autoantibodies cause the gastrointestinal dysfunction.


METHODS
We used isolated mouse colon undergoing colonic migrating motor complex (MMC) activity to test for autoantibodies that disrupt colonic motility. Purified immunoglobulin G (IgG) from patients with type 1 diabetes or from controls was tested either in vitro or after passive transfer. Pharmacological studies of the interaction between the IgG and L-type calcium channel activator (Bay K8644) and inhibitors (nicardipine and verapamil) were performed. The effect of IgG on nerve-evoked contraction of the vas deferens longitudinal smooth muscle was also assessed.


RESULTS
MMC activity was disrupted by IgG (0.2 mg/mL) from 8 of 16 patients with type 1 diabetes but not by control IgG. Passive transfer of diabetic IgG to mice also disrupted MMCs, showing access to the antigen in vivo. The acute effect of the autoantibody was mimicked by the dihydropyridine agonist, Bay K8644 (2-10 nmol/L), and both Bay K8644 and the autoantibody competitively inhibited the effect on MMC contraction of the dihydropyridine antagonist, nicardipine. Diabetic IgG, but not control IgG, altered the nerve-evoked contractile activity of vas deferens smooth muscle effects mimicked by Bay K8644.


CONCLUSIONS
A novel functional autoantibody that activates smooth muscle L-type calcium channels at the dihydropyridine binding site is produced specifically by patients with type 1 diabetes and may mediate gastrointestinal and autonomic dysfunction in these patients.
Department of Immunology, Allergy and Arthritis, Flinders Medical Centre, Adelaide, South Australia, Australia. michael.jackson@flinders.edu.au
Michael W
MW
Jackson
Tom P
TP
Gordon
Sally A
SA
Waterman
D000328:Adult; D000368:Aged; D000818:Animals; D001323:Autoantibodies / Q000187:drug effects / Q000494:pharmacology*; D001665:Binding Sites; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D003106:Colon / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000503:physiopathology*; D004095:Dihydropyridines / Q000378:metabolism; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D007410:Intestinal Diseases / Q000276:immunology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016065:Myoelectric Complex, Migrating / Q000187:drug effects; D014649:Vas Deferens / Q000378:metabolism
D001323:Autoantibodies; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; C038806:1,4-dihydropyridine