Identification of Autoantibody-Negative Autoimmune Type 2 Diabetic Patients

Abstract

OBJECTIVEIslet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with β-cell function.RESEARCH DESIGN AND METHODSAdult phenotypic type 2 diabetic patients (n = 36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma-associated protein-2 autoantibody, and zinc transporter autoantibody).RESULTSWe identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab−T−, Ab+T−, Ab−T+, and Ab+T+). The Ab−T+ type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab+T+ type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses.CONCLUSIONSWe have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab−T+ and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated.

The potential role of glutamate in the current diabetes epidemic

“…On the other hand, T2D occurs also in children [2,3,12] and sometimes with keto-acidosis [13]. Moreover, a considerable subgroup of adult and pediatric T2D subjects present evidence of humoral and cellular b-cell autoimmunity [14][15][16][17][18] that is more common than previously thought and that may contribute significantly to the progressive decline in b-cell function observed in T2D patients. In addition, obesity and insulin resistance are now recognized risk factors also for T1D [19][20][21], and it is also emerging that islet inflammation can be present in T2D [22,23].…”

Autoimmune Aspects of Type 2 Diabetes Mellitus - A Mini-Review

“…BrooksWorrell et al [43] demonstrated that islet-reactive T cells can be found in phenotypic T2DM patients and the presence of such cells is associated with a more severe β-cell 194 lesion and lower residual insulin secretion. They established an assay to measure T-cell reactivity to islet antigens and discovered the existence of a T-cell population responsive to several islet antigens in LADA patients but also phenotypic T2DM patients without autoantibodies [43] . This crucial finding is another important link between autoimmunity and T2DM.…”

Humoral Autoimmunity in Type 1 Diabetes: Prediction, Significance, and Detection of Distinct Disease Subtypes

“…The immunological diagnosis of LADA relies primarily on the detection of autoantibodies against GAD65 in the serum of clinically diagnosed T2D patients who also show impaired insulin secretion and a high frequency of being on insulin treatment. Additionally, it has been previously reported that LADA patients possess T cells reactive to islet proteins as is also the case in "canonical" type 1 diabetes, in contrast to classic autoantibody-negative T2D patients (Brooks-Worrell et al 2011).…”