Check GAD antibody positivity with the Diamyd anti-GAD RIA plate*

ICA properly, Dr. Tuomi was able to point outthat the ICA assays had been performed in hislaboratory!We then had a vigorous debate on what weshould call this slow-onset Type 1 diabetes. LeifGroop favoured the term AIDA (autoimmunediabetes in adults) and PZ suggested SODA(slow onset diabetes of adults), but the wisdomand status of IM prevailed and we adopted theterm LADA (latent immune diabetes in adults),not to be confused with the Mexican telephonecompany or the Czech motor car! Tuomi quicklywrote up the results and submitted the paperto Diabetes – it was accepted within 5 days.With a number of other studies with internationalcollaborators we were able to confirm ourfindings in several different countries and ethnicgroups. The biggest challenge still lay ahead. Wewere battling against the ICA “mafia” who stillbelieved that this test was the gold standard.Would it be feasible to use the anti-GAD test topredict future diabetes?We then came again through serendipity to astudy we called “Back to the Future”.Fortuitously, my colleague in Finland, ProfessorJaakko Tuomilehto, brought to our attentionthat the Finnish Women’s Register had takenblood samples from every woman during pregnancysince 1984 and these samples were storedaway at the National Finnish Public HealthInstitute. By linking these samples to the FinnishType 1 Diabetes Register, and testing them allfor anti-GAD, we were able to show that up to10 years prior to a woman developing Type 1diabetes, antibodies to GAD were present. Thiswas a critical study that confirmed the utility ofthe anti-GAD test as a powerful weapon for theprediction of Type 1 diabetes, and establishedthat the “latent period” for an autoimmune diseasecould be very long indeed.Later, in a landmark collaboration with thelate Professor Robert Turner on the UKPDScohort, we were able to demonstrate that 10% ofthe “pedigree” Type 2 diabetics of this cohortactually had LADA. It is now well demonstratedthat this 10% figure applies in many countriesaround the world in terms of the number ofsubjects “misclassified” as having Type 2 diabetes.Of course, early prediction of Type 1 diabetesin its long preclinical phase is not that much of“It is now welldemonstrated that this 10%figure applies in many countriesaround the world interms of the number of subjects“misclassified” as”having Type 2 diabetesa blessing in the absence of an effective preventiveregimen. At the time of our studies onLADA referred to above, there was a peaking ofinterest in administration of autoantigenic preparationsmucosally (oral tolerance) to abrogateautoimmune disorders diabetes included.Administration of GAD to NOD mice to retardonset of diabetes, in our studies and those ofothers, have given at best “promising” results.While earlier enthusiasm for oral tolerance maybe diminishing, we certainly look forward toseeing results of human trials of the preventativeuse of GAD in LADA.Paul Zimmet isDirector of theInternationalDiabetes Instituteand Professor ofDiabetes, MonashUniversity inMelbourne, Australia.His current research includes Type 1 diabetesetiology and the molecular mechanismsof Type 2 diabetes, insulin resistance andobesity and the effects of life-style changeleading to diabetes, obesity, coronary heartdisease and hypertension in developingcountries in the Asia-Pacific region.Intraperitoneal injection of GAD65prevents diabetes in NOD mice100 NaClMBPGAD-MBP8060402000 10 20 30GADtreatment Age (weeks)Pleau et al. (1995). Prevention of autoimmunediabetes in nonobese diabetic female mice bytreatment with recombinant glutamic aciddecarboxylase (GAD65). Clin Immunol Pathol76:90-95Diabetic animals %Stimulation index log100101GAD in Graphs• 4 wk old NOD mice which hadbeen injected ip 3 times with GAD65were protected from diabetes developmentcompared to mice injectedwith fusion protein (MBP) or saline(NaCl)• ip administration of GAD65prevents diabetesGAD65 is a key target antigen in theinduction of murine IDDMGADhsp65cbphinsulin3 4 6 8 12 15Age of mice (weeks)Kaufman et al. (1993) Spontaneous loss of T celltolerance to glutamic acid in murine insulindependentdiabetes. Nature 366:69-72• Spontaneous T cell proliferativeresponses in NOD micefirst develop to GAD65, then tohsp65, carboxypeptidase H andto insulin in a defined order.• GAD65 is a key diabetogenicautoantigen in murine IDDMdmccad june 2003page 35