Targeting Type 1 Diabetes: Selective Approaches for New Therapies

Abstract

The clinical onset of type 1 diabetes is characterized by the destruction of the insulin-producing β cells of the pancreas and is caused by autoantigen-induced inflammation (insulitis) of the islets of Langerhans. The current standard of care for type 1 diabetes mellitus patients allows for management of the disease with exogenous insulin, but patients eventually succumb to many chronic complications such as limb amputation, blindness, and kidney failure. New therapeutic approaches now on the horizon are looking beyond glycemic management and are evaluating new strategies from protecting and regenerating endogenous islets to treating the underlying autoimmunity through selective modulation of key immune cell populations. Currently, there are no effective treatments for the autoimmunity that causes the disease, and strategies that aim to delay or prevent the onset of the disease will play an important role in the future of diabetes research. In this review, we summarize many of the key efforts underway that utilize molecular approaches to selectively modulate this disease and look at new therapeutic paradigms that can transform clinical treatment.

Figure 1.

Progression of β cell loss and primary cells involved in the pathogenesis of T1DM. Predisposition from bone marrow, thymus, and immune populations followed by a precipitating event lead to β cell mass loss prior to clinical diagnosis and therapeutic intervention.

Figure 2.

Selective T1DM pre-clinical and clinical therapeutic intervention strategies through immunoregulation, β cell protection and regeneration, and antigenic therapy. Solid arrows denote a causal event. Dashed arrows denote cell population shift. Red arrows indicate the pathway leads to T1DM autoimmunity and green arrows indicated protective and immune tolerance pathways. Green text indicates increase secretion or strengthening of indicated molecular interaction. Red text indicates suppression of indicated molecular interaction. Purple text indicates additional therapies discussed herein.

Figure 3.

Future therapeutic paradigm for localized early delivery of therapeutics for T1DM. In combination with genetic screening and early biomarker T1DM indication, formulated nanoparticles with encapsulated therapeutic agent can be conjugated to islet targeting agents that populate the nanoparticle surface. These localized delivery agents will likely need to be used in combination therapies.