Disease-Modifying Therapies in Type 1 Diabetes: A Look into the Future of Diabetes Practice.

The novel understanding that the presence of multiple islet autoantibodies, indicating islet autoimmunity, inevitably leads to type 1 diabetes mellitus (T1DM) has necessitated the development of a new staging classification system for the condition. Coupled with an improved understanding of the disease course, the realization that T1DM appears to be more heterogeneous than previously thought has led to unique opportunities to develop more targeted therapies that may be applied even before the onset of dysglycemia or symptoms. To date, several therapies have been trialed to delay or halt disease progression in both presymptomatic and clinical T1DM, each demonstrating varying degrees of effectiveness, toxicity, and utility. Key research supports the eventual implementation of immunotherapy in autoimmune diabetes, potentially calling for a paradigm shift among care providers. It will likely be necessary to develop new approaches to trial design and to address potential barriers to progress before an effective treatment for the disease may be achieved.

Emerging Concepts on Disease-Modifying Therapies in Type 1 Diabetes.

PURPOSE OF REVIEW: This review seeks to characterize emerging concepts related to disease-modifying therapy in type 1 diabetes. RECENT FINDINGS: We begin by describing the new understanding that islet autoimmunity, as identified by the presence of islet autoantibodies, inevitably leads to clinical type 1 diabetes. This understanding informs the new staging paradigm for type 1 diabetes, which suggests that type 1 diabetes may be recognized and diagnosed long before symptoms develop. Although it is known that nearly all individuals with established islet autoimmunity will eventually develop symptomatic type 1 diabetes (T1D), individual characteristics such as age and biomarker profile may predict rate of disease progression and response to treatment and may therefore be used to individualize therapy. Key research supports the use of immunotherapy in TID, although a paradigm shift is necessary before immunotherapy may transition from clinical trials to clinical practice. Recent and ongoing research as it relates to these concepts is described throughout.

Residual C-peptide in type 1 diabetes: what do we really know?

Connecting peptide, or C-peptide, is a protein that joins insulin's α and B chains in the proinsulin molecule. During insulin synthesis, C-peptide is cleaved from proinsulin and secreted in an equimolar concentration to insulin from the ß cells. Because C-peptide experiences little first-pass clearance by the liver, and because levels are not affected by exogenous insulin administration, it may be used as a marker of endogenous insulin production and a reflection of ß-cell function. Residual ß-cell function, as measured by C-peptide in those with type 1 diabetes (T1D), has repeatedly been demonstrated to be clinically important. The Eisenbarth model of type 1 diabetes postulated immune-mediated linear loss of ß cells, with clinical diagnosis occurring when there was insufficient insulin secretion to meet glycemic demand. Moreover, the model also implied that all individuals with T1D rapidly and inevitably progressed to absolute insulin deficiency. Correspondingly, it was assumed that most people with longstanding T1D would show little to no residual C-peptide secretion. While more than a quarter century of data confirms that this model remains largely true and appropriately serves as the basis for prevention studies, accumulating evidence suggests that the natural history of ß-cell function before, during and after diagnosis is more complex. In this review, we discuss the clinical benefits of residual insulin secretion and present recent data about the natural history of insulin secretion in those with, or at risk for T1D.