Relapsing/remitting type 1 diabetes

Abstract

Aims/hypothesis: Type 1 diabetes is believed to be an autoimmune disease associated with irreversible loss of insulin secretory function that follows a chronic progressive course. However, it has been speculated that relapsing/remitting disease progression may occur in type 1 diabetes.

Methods: We report the case of an 18-year-old girl with Graves' disease, chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple islet autoantibodies, presenting with relapsing/remitting hyperglycaemia. Peripheral blood mononuclear cells were analysed for islet autoimmunity.

Results: There were two instances of hyperglycaemia relapse during CIDP flare-ups that required insulin therapy and remitted after i.v. immunoglobulin (IVIG) therapy improving neurological symptoms. A diagnosis of type 1 diabetes was assigned on the basis of insulin need, HbA_1c and islet autoantibodies. Insulin requirements disappeared following IVIG treatment and peaked during CIDP flare-ups. Pro- and anti-inflammatory cytokine responses were noted against islet autoantigens.

Conclusions/interpretation: We provide clinical evidence of relapsing/remitting type 1 diabetes associated with IVIG treatment and the regulation of islet autoimmunity. Despite sufficient residual beta cell mass, individuals can experience episodes of impaired glycaemia control. This disconnect between beta cell mass and function highlighted by our case may have implications for the use of beta cell function as the primary endpoint for immune intervention trials aiming to protect beta cell mass rather than function. Immune modulation may restore beta cell function and glycaemic control.

Keywords: Autoimmune disease; Immune regulation; Immunotherapy; Type 1 diabetes.

Fig. 1

Time course of CIDP disease progression, immunotherapy and type 1 diabetes as defined by insulin need and HbA_1c (a). During the patient’s most recent flare-up of CIDP, a blood sample was drawn and analysed for T cell reactivity to the islet autoantigens PPI, IA-2 and GAD65 (GAD), as well as T cell responses to tetanus toxoid (TT) as a control for recall immunity to a vaccine antigen unrelated to type 1 diabetes (b–f). Proliferative responses to PPI were suppressed despite proinflammatory (IFN-γ, IL-17) and anti-inflammatory cytokine production in response to this islet antigen. T cells responded both to IA-2 by proliferation and cytokines, whereas no T cell responses were detectable against GAD65 despite the presence of serum autoantibodies against this protein (not shown). Dashed red arrows indicate IVIG administration. The timeline starts on September 2014 (t = 0 months) and ends on May 2016 (t = 20 months). The clinical course of CIDP is depicted as a red graded fill, in which the more intensely red areas are flare-ups and white areas are periods of remission. To convert values for HbA_1c in mmol/mol into % units, multiply by 0.0915 and add 2.15. Proliferation was normalised to the response in control wells with culture medium and human serum, i.e. without a diabetes-associated antigen (9.5 ± 1.0 [SD] cpm × 10³). Cytokine production in control wells was as follows (in ng/ml): IFN-γ, 0.059; IL-17, 0.003; IL-13, 0.006; IL-10, 0.026