Autoimmunity to CD38 and GAD in Type I and Type II diabetes: CD38 and HLA genotypes and clinical phenotypes

Abstract

Aims/hypothesis. Autoantibodies against CD38 have been found in some patients with Type II (non-insulindependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i) overlaps with anti-GAD autoimmunity, (ii) identifies an insulin-deficient phenotype, (iii) is under the influence of genetic factors. Methods. We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects).Results. CD38-autoantibodies were found in 8.4% of Type II diabetic patients (p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD38ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti-CD38 positive had DQB1*02 compared with 38% of anti-CD38 negative (p=0.04).On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired (p=0.02) only in association with anti-GAD positivity (3.2±3.1 U/mol, mean ± SD) but not in anti-CD38 positive patients (5.6±2.9) as compared with patients free of autoimmunity (4.5±4.6, p=NS).In 44 Type II diabetic patients (22 negative and 22 positive for anti-CD38), no mutations were detected in any of the 8 exons, 5′ end of intron 1 or the 5′ and 3′ untranslated regions of the CD38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype. Conclusion. Anti-CD38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence. [Diabetologia (2002[Diabetologia ( ) 45:1298[Diabetologia ( -1306

CD38 polymorphisms in Spanish patients with systemic lupus erythematosus

“…However, no individual bearing T in this position was detected among our patients with SLE, nor did our healthy controls. These results, together those obtained in Italian studies [20,25], support the absence (or the extremely low frequency) of this polymorphism in white population.…”

Autoimmune thyroid disorders

“…The abovementioned study underlines the importance of a common genetic susceptibility in patients with AITD and T1D, as confirmed also in other studies [81].…”

Suppressed Insulin Signaling and Increased Apoptosis inCd38-Null Islets

“…Comparing our findings with the results of Okamoto and colleagues (20) illustrates the potentially critical role of genetic background in the susceptibility to diabetes in Cd38 knockout mice. Indeed, the CD38 mutation seen in Japanese patients (23) was not observed in a European cohort (24). We await reports from large-scale human genetic studies to clarify the role of variation in the CD38 gene in type 1 and type 2 diabetes.…”

“…In one report (23), a missense mutation in CD38 was associated with diabetes in a small number of Japanese patients, although this was not seen in a European study (24). Diabetic ob/ob mice have dramatically reduced CD38 mRNA expression (25).…”