Anti-CD38 autoantibodies in type? diabetes

Abstract

Human diabetes mellitus comprises two main clinical entities: type 1 and type 2 diabetes. While type 1 diabetes is autoimmune in origin, type 2 diabetes is due to a decreased sensitivity to insulin action (so-called insulin resistance) associated with impaired beta cell function. However, it is becoming increasingly clear that there is a certain overlap between these two diseases. While some degree of insulin resistance is present in type 1 diabetic patients, markers of beta cell autoimmunity (either primary or secondary) can frequently be detected in type 2 diabetic subjects. In this scenario, anti-CD38 autoantibodies (aAbs) have been described in both type 1 and type 2 diabetic patients. Contrary to the other known islet aAbs, anti-CD38 autoantibodies are more prevalent in long-standing than in new-onset type 1 diabetes, and more prevalent in type 2 than in type 1 diabetes. Moreover, anti-CD38 aAbs are endowed with unique stimulatory properties on Ca(2+) mobilization and insulin secretion. These observations suggest that autoimmunity may be both the cause and consequence of beta cell dysfunction, in either case imposing a further toll for the control of glucose homeostasis.

Fig. 1

The natural evolution of insulin sensitivity and insulin secretion in different metabolic situations and with progression to type 2 diabetes (T2D).

Fig. 2

Structure of human CD38.

Fig. 3

Western blot analysis of CD38 on isolated human islet cells, as compared to CD38 expressed on thymocytes, the Jurkat T cell line and human endothelial cells (HEC, negative control).

Fig. 4

The Okamoto model of CD38-mediated insulin secretion. On the left, the classical model proposed by Ashcroft is depicted. See text for details.

Fig. 5

Prevalence and titers of anti-CD38 autoantibodies in different diabetic cohorts and corresponding control healthy groups matched for age and gender.

Fig. 6

Agonistic activity of anti-CD38⁺ sera on Ca²⁺ release in Jurkat T cells. A, agonistic anti-CD38⁺ serum. B, the same serum after preincubation with protein G-sepharose to remove the Ig fraction. C, the same serum after preincubation with recombinant soluble CD38 to block the CD38-specific Ig fraction. Data are presented as density plots of the shift in the fluorescence of the Ca²⁺-sensitive dye Fluo-3 over a 8.5 min time course.

Fig. 7

Possible pathogenic effects of anti-CD38 autoantibodies. The parts depicted in grey are currently speculative only. See text for details.

Fig. 8

Relative contributions of insulin resistance and beta cell autoimmunity to different forms of diabetes, and the corresponding prevalence of anti-CD38 autoantibodies.