Impact of islet autoimmunity on the progressive β-cell functional decline in type 2 diabetes

Abstract

Objective: Cross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.

Research design and methods: Twenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits.

Results: Of the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab-T-), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses.

Conclusions: These pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline.

Figure 1

Longitudinal islet-specific T-cell responses for six Ab−T− T2D patients (A) and seven Ab−T+ T2D patients (B). The horizontal line at three blot sections represents the cutoff for T-cell positivity.

Figure 2

Longitudinal islet Ab responses for two Ab+T− T2D patients. A: Both patients developed IA-2 positivity, and one patient developed both IA-2 and GADA. B: GADA results. The horizontal lines show the cutoff for positive responses.

Figure 3

A:Five T2D patients developed both islet-specific T-cell reactivity and islet Abs during follow-up (Ab+T+). All five patients were GADA+ (B), and one patient was also IA-2+ (C). The horizontal lines show the cutoff for positive responses.

Figure 4

Median percentage change in FCP levels (A) and glucagon-SCP (B) responses for the nonautoimmune patients (Ab−T−) and patients developing islet autoimmunity (Ab+T−, Ab-T+, and Ab+T+) before and after autoimmune development.